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Nair B, Menon A, Rithwik Kalidas M, Nath LR, Calina D, Sharifi-Rad J. Modulating the JAK/STAT pathway with natural products: potential and challenges in cancer therapy. Discov Oncol 2025; 16:595. [PMID: 40268770 DOI: 10.1007/s12672-025-02369-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 04/11/2025] [Indexed: 04/25/2025] Open
Abstract
The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway is a critical signaling network governing cellular functions such as immune responses, proliferation, and apoptosis. Dysregulation of this pathway is strongly implicated in cancer progression. This review explores the therapeutic potential of natural products, including Curcumin, Resveratrol, Apigenin, and Epigallocatechin Gallate (EGCG), as modulators of the JAK/STAT pathway. These phytochemicals exhibit anticancer activity by inhibiting JAK/STAT phosphorylation, blocking STAT dimerization, and interfering with STAT-DNA binding. A systematic evaluation of included peer-reviewed studies highlights their promise as complementary agents to conventional cancer therapies. However, challenges such as poor bioavailability and the need for robust clinical validation remain significant hurdles. Addressing these limitations through advanced drug delivery systems and rigorous trials could unlock their full potential in cancer treatment.
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Affiliation(s)
- Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
| | - Anjana Menon
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
- Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
| | - M Rithwik Kalidas
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
- Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara, P.O., Kochi, Kerala, 682041, India.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
| | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, 092301, Ecuador.
- Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
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Millot P, Duquesne L, San C, Porte B, Pujol C, Hosten B, Hugon J, Paquet C, Mouton-Liger F. Non-canonical STAT3 pathway induces alterations of mitochondrial dynamic proteins in the hippocampus of an LPS-induced murine neuroinflammation model. Neurochem Int 2025; 186:105979. [PMID: 40209854 DOI: 10.1016/j.neuint.2025.105979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/26/2025] [Accepted: 04/07/2025] [Indexed: 04/12/2025]
Abstract
The activation of STAT3 is a crossroads of cellular regulation, induced in its canonical pathway by phosphorylation on a critical tyrosine residue (Y705). The existence of a STAT3 non-canonical signaling mechanisms, induced by phosphorylation at serine 727 (S727), has been recently identified in vitro. After cytoplasmic activation, non-canonical STAT3 could move to the level of mitochondria-endoplasmic reticulum contacts (MERCs). We have previously shown that LPS injections in mouse model induce STAT3 canonical pathway, leading to its nuclear translocation and to neuroinflammation. However, the effects of LPS on activation of the non-canonical pathway and its consequences on protein complexes of MERCs remain to be determined. In an in vivo LPS mouse model, we found that systemic inflammation induces in hippocampus the non-canonical STAT3 pathway. LPS-induced STAT3 affects specifically MERC protein BAP31, and that of a mitochondrial membrane protein known to interact with it, TOM40. These findings shed light on the role of STAT3 on mitochondrial - endoplasmic reticulum interaction under inflammatory conditions, offering new perspectives for targeting mitochondrial function and STAT3 activation in disease contexts.
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Affiliation(s)
- Périne Millot
- Université Paris Cité, Institut Pasteur, AP-HP, INSERM OTEN, UMRS 1144, CNRS, Fondation Pour l'Audition, IHU reConnect, F-75006, Paris, France
| | - Laurine Duquesne
- Université Paris Cité, Institut Pasteur, AP-HP, INSERM OTEN, UMRS 1144, CNRS, Fondation Pour l'Audition, IHU reConnect, F-75006, Paris, France
| | - Carine San
- Université Paris Cité, Institut Pasteur, AP-HP, INSERM OTEN, UMRS 1144, CNRS, Fondation Pour l'Audition, IHU reConnect, F-75006, Paris, France; Unité Claude Kellershohn, Institut de Recherche Saint-Louis, APHP Nord Université de Paris Cité, Saint Louis Hospital, Paris, France
| | - Baptiste Porte
- Université Paris Cité, Institut Pasteur, AP-HP, INSERM OTEN, UMRS 1144, CNRS, Fondation Pour l'Audition, IHU reConnect, F-75006, Paris, France
| | - Claire Pujol
- Mitochondrial Biology Group, Institut Pasteur, CNRS UMR 3691, 75015, Paris, France
| | - Benoit Hosten
- Université Paris Cité, Institut Pasteur, AP-HP, INSERM OTEN, UMRS 1144, CNRS, Fondation Pour l'Audition, IHU reConnect, F-75006, Paris, France; Unité Claude Kellershohn, Institut de Recherche Saint-Louis, APHP Nord Université de Paris Cité, Saint Louis Hospital, Paris, France
| | - Jacques Hugon
- Université Paris Cité, Institut Pasteur, AP-HP, INSERM OTEN, UMRS 1144, CNRS, Fondation Pour l'Audition, IHU reConnect, F-75006, Paris, France; Centre de Neurologie Cognitive, AP-HP.Nord, Site Lariboisière Fernand-Widal, Paris, France
| | - Claire Paquet
- Université Paris Cité, Institut Pasteur, AP-HP, INSERM OTEN, UMRS 1144, CNRS, Fondation Pour l'Audition, IHU reConnect, F-75006, Paris, France; Centre de Neurologie Cognitive, AP-HP.Nord, Site Lariboisière Fernand-Widal, Paris, France
| | - François Mouton-Liger
- Université Paris Cité, Institut Pasteur, AP-HP, INSERM OTEN, UMRS 1144, CNRS, Fondation Pour l'Audition, IHU reConnect, F-75006, Paris, France.
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Aksu AM, Akter A, Dhillon P, Zerbel ZJ, Bridge-Comer PE, Gbayisomore O, Reilly SM. JNK mediates serine phosphorylation of STAT3 in response to fatty acids released by lipolysis. RESEARCH SQUARE 2025:rs.3.rs-6150649. [PMID: 40092442 PMCID: PMC11908360 DOI: 10.21203/rs.3.rs-6150649/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Adipocytes play an essential role in energy balance and metabolic health. Excess nutrients are stored within the white adipose tissue (WAT) as triglycerides. Energetic demand is communicated to the adipocyte by the sympathetic nervous system. Catecholamines released by nerve terminals in the adipose tissue promote lipolysis, a process in which triglycerides are broken down into fatty acids and glycerol. Lipolytic activation of white adipocytes is associated with an increase in the rate of oxygen consumption. This lipolysis induced respiration requires phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Ser727. This study identifies c-Jun N-terminal kinase 1 (JNK1) as the kinase responsible for this critical phosphorylation event, and thus a key regulator of lipolysis-driven oxidative metabolism. We demonstrate that JNK1 is activated in response to intracellular fatty acids released during lipolysis and phosphorylates lipid droplet-associated STAT3, leading to inhibition of glycerol-3-phosphate acyltransferase 3 (GPAT3) and suppression of fatty acid re-esterification. This mechanism promotes uncoupled mitochondrial respiration, increasing energy expenditure. Inhibition of JNK1 attenuated oxidative metabolism without affecting the rate of lipolysis. The MAP kinase cascade upstream of JNK1 in lipolytic adipocytes remains unclear. Neither apoptosis signal-regulating kinase 1 (ASK1) nor mitogen-activated protein kinase kinases 4/7 (MKK4/7) appear to be required. Our findings suggest that JNK1 functions as a metabolic sensor in adipocytes, activating oxidative metabolism through STAT3 phosphorylation in response to fatty acids, with implications for energy balance and obesity-related metabolic regulation.
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Yang X, Yang J, Zhou Q, Kang L, Li X, Guo W, Li F, Deng Y. Protocatechuic aldehyde ameliorates psoriasis-like skin inflammation and represses keratinocyte-derived IL-1α and CXCL9 via inhibiting STAT3 activation. Int Immunopharmacol 2025; 147:114037. [PMID: 39793224 DOI: 10.1016/j.intimp.2025.114037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/27/2024] [Accepted: 01/04/2025] [Indexed: 01/13/2025]
Abstract
Psoriasis is a chronic inflammatory skin disease. Consistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) in epidermal keratinocyte transactivates various keratinocyte-derived pro-inflammatory cytokines and elicits spontaneous psoriasis-like skin inflammation. In the current study, we first report that topical application of protocatechuic aldehyde (PA), the bioactive compound from Salvia miltiorrhiza (Danshen), significantly improved psoriasis-like skin symptoms and reduced immune cell infiltration in psoriatic lesions. Further molecular mechanism studies demonstrated that PA inactivated STAT3 and inhibited STAT3-mediated transactivation of interleukin-1α (IL-1α) and C-X-C motif chemokine ligand 9 (CXCL9) in epidermal keratinocyte both in vivo and in vitro. Knockdown of STAT3 attenuated the repression effect on IL-1α and CXCL9 by PA. Our results suggested that PA repressed the transactivation of IL-1α and CXCL9 through inhibiting STAT3 in keratinocyte. PA could be potentially used for psoriasis topical treatment or be as a lead compound for drug development.
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Affiliation(s)
- Xiaoxuan Yang
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106 China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106 China; School of Food and Biological Engineering, Chengdu University, Chengdu 610106 China
| | - Jie Yang
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106 China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106 China; School of Pharmacy, Chengdu University, Chengdu 610106 China
| | - Qian Zhou
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106 China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106 China; School of Food and Biological Engineering, Chengdu University, Chengdu 610106 China
| | - Liang Kang
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106 China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106 China; School of Food and Biological Engineering, Chengdu University, Chengdu 610106 China
| | - Xiaoya Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106 China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106 China; School of Food and Biological Engineering, Chengdu University, Chengdu 610106 China
| | - Wanjun Guo
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437 China
| | - Fulun Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437 China.
| | - Yu Deng
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu 610106 China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu 610106 China; School of Basic Medical Sciences, Chengdu University, Chengdu 610106 China.
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Manoharan S, Perumal E. A strategic review of STAT3 signaling inhibition by phytochemicals for cancer prevention and treatment: Advances and insights. Fitoterapia 2024; 179:106265. [PMID: 39437855 DOI: 10.1016/j.fitote.2024.106265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024]
Abstract
Cancer remains a significant global health concern. The dysregulation of signaling networks in tumor cells greatly affects their functions. This review intends to explore phytochemicals possessing potent anticancer properties that specifically target the STAT3 signaling pathway, elucidating strategies and emphasizing their potential as promising candidates for cancer therapy. The review comprehensively examines various STAT3 inhibitors designed to disrupt the signaling cascade, including those targeting upstream activation, SH2 domain phosphorylation, DNA binding domain (DBD), N-terminal domain (NTD), nuclear translocation, and enhancing endogenous STAT3 negative regulators. A literature review was conducted to identify phytochemicals with anticancer activity targeting the STAT3 signaling pathway. Popular research databases such as Google Scholar, PubMed, Science Direct, Scopus, Web of Science, and ResearchGate were searched from the years 1989 - 2023 based on the keywords "Cancer", "STAT3", "Phytochemicals", "Phytochemicals targeting STAT3 signaling", "upstream activation of STAT3", "SH2 domain of STAT3", "DBD of STAT3", "NTD of STAT3, "endogenous negative regulators of STAT3", or "nuclear translocation of STAT3", and their combinations. A total of 264 relevant studies were selected and analyzed based on the mechanisms of action and the efficacy of the phytocompounds. The majority of the discussed phytochemicals primarily focus on inhibiting upstream activation of STAT3. Additionally, flavonoid and terpenoid compounds exhibit multifaceted effects by targeting one or more checkpoints within the STAT3 pathway. Analysis reveals that phytochemicals targeting upstream activation predominantly belong to the classes of flavonoids and terpenoids, which hold significant promise as effective anticancer therapeutics. Future research in this field can be directed towards exploring and developing these scrutinized classes of phytochemicals to achieve desired therapeutic outcomes in cancer treatment.
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Affiliation(s)
- Suryaa Manoharan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
| | - Ekambaram Perumal
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India.
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He X, Liu P, Luo Y, Fu X, Yang T. STATs, promising targets for the treatment of autoimmune and inflammatory diseases. Eur J Med Chem 2024; 277:116783. [PMID: 39180944 DOI: 10.1016/j.ejmech.2024.116783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 08/14/2024] [Accepted: 08/16/2024] [Indexed: 08/27/2024]
Abstract
Cytokines play a crucial role in the pathophysiology of autoimmune and inflammatory diseases, with over 50 cytokines undergoing signal transduction through the Signal Transducers and Activators of Transcription (STAT) signaling pathway. Recent studies have solidly confirmed the pivotal role of STATs in autoimmune and inflammatory diseases. Therefore, this review provides a detailed summary of the immunological functions of STATs, focusing on exploring their mechanisms in various autoimmune and inflammatory diseases. Additionally, with the rapid advancement of structural biology in the field of drug discovery, many STAT inhibitors have been identified using structure-based drug design strategies. In this review, we also examine the structures of STAT proteins and compile the latest research on STAT inhibitors currently being tested in animal models and clinical trials for the treatment of immunological diseases, which emphasizes the feasibility of STATs as promising therapeutic targets and provides insights into the design of the next generation of STAT inhibitors.
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Affiliation(s)
- Xinlian He
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Pingxian Liu
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Youfu Luo
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyuan Fu
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tao Yang
- Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Clements AN, Casillas AL, Flores CE, Liou H, Toth RK, Chauhan SS, Sutterby K, Deshmukh SK, Wu S, Xiu J, Farrell A, Radovich M, Nabhan C, Heath EI, McKay RR, Subah N, Centuori S, Wheeler TJ, Cress AE, Rogers GC, Wilson JE, Recio-Boiles A, Warfel NA. Inhibition of PIM kinase in tumor associated macrophages suppresses inflammasome activation and sensitizes prostate cancer to immunotherapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.21.618756. [PMID: 39484473 PMCID: PMC11526960 DOI: 10.1101/2024.10.21.618756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Immunotherapy has changed the treatment paradigm for many types of cancer, but immune checkpoint inhibitors (ICIs) have not shown benefit in prostate cancer (PCa). Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment (TME) and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. Here, we identify PIM kinases as important regulators of inflammasome activation in tumor associated macrophages (TAMs). Analysis of clinical data from a cohort of treatment naïve, hormone responsive PCa patients revealed that tumors from patients with high PIM1/2/3 display an immunosuppressive TME characterized by high inflammation (IL-1β and TNFα) and a high density of repressive immune cells, most notably TAMs. Strikingly, macrophage-specific knockout of PIM reduced tumor growth in syngeneic models of prostate cancer. Transcriptional analyses indicate that eliminating PIM from macrophages enhanced the adaptive immune response and increased cytotoxic immune cells. Combined treatment with PIM inhibitors and ICIs synergistically reduced tumor growth. Immune profiling revealed that PIM inhibitors sensitized PCa tumors to ICIs by increasing tumor suppressive TAMs and increasing the activation of cytotoxic T cells. Collectively, our data implicate macrophage PIM as a driver of inflammation that limits the potency of ICIs and provides preclinical evidence that PIM inhibitors are an effective strategy to improve the efficacy of immunotherapy in prostate cancer.
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Liao S, Deng J, Deng M, Chen C, Han F, Ye K, Wu C, Pan L, Lai M, Tang Z, Zhang H. AFDN Deficiency Promotes Liver Tropism of Metastatic Colorectal Cancer. Cancer Res 2024; 84:3158-3172. [PMID: 39047222 DOI: 10.1158/0008-5472.can-23-3140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 05/09/2024] [Accepted: 07/16/2024] [Indexed: 07/27/2024]
Abstract
Liver metastasis is a major cause of morbidity and mortality in patients with colorectal cancer. A better understanding of the biological mechanisms underlying liver tropism and metastasis in colorectal cancer could help to identify improved prevention and treatment strategies. In this study, we performed genome-wide CRISPR loss-of-function screening in a mouse colorectal cancer model and identified deficiency of AFDN, a protein involved in establishing and maintaining cell-cell contacts, as a driver of liver metastasis. Elevated AFDN expression was correlated with prolonged survival in patients with colorectal cancer. AFDN-deficient colorectal cancer cells preferentially metastasized to the liver but not in the lungs. AFDN loss in colorectal cancer cells at the primary site promoted cancer cell migration and invasion by disrupting tight intercellular junctions. Additionally, CXCR4 expression was increased in AFDN-deficient colorectal cancer cells via the JAK-STAT signaling pathway, which reduced the motility of AFDN-deficient colorectal cancer cells and facilitated their colonization of the liver. Collectively, these data shed light on the mechanism by which AFDN deficiency promotes liver tropism in metastatic colorectal cancer. Significance: A CRISPR screen reveals AFDN loss as a mediator of liver tropism in colorectal cancer metastasis by decreasing tight junctions in the primary tumor and increasing interactions between cancer cells and hepatocytes.
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Affiliation(s)
- Shaoxia Liao
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
- Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, China
| | - Jingwen Deng
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengli Deng
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
| | - Chaoyi Chen
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Fengyan Han
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Kehong Ye
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
| | - Chenxia Wu
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
| | - Lvyuan Pan
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
| | - Maode Lai
- Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, China
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhe Tang
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Honghe Zhang
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
- Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, China
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou, China
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Weng C, Xu J, Ying X, Sun S, Hu Y, Wang X, He C, Lu B, Li M. The PDIA3-STAT3 protein complex regulates IBS formation and development via CTSS/MHC-II pathway-mediated intestinal inflammation. Heliyon 2024; 10:e36357. [PMID: 39286134 PMCID: PMC11403428 DOI: 10.1016/j.heliyon.2024.e36357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/06/2024] [Accepted: 08/14/2024] [Indexed: 09/19/2024] Open
Abstract
Irritable bowel syndrome (IBS) is a persistent functional gastrointestinal disorder characterised by abdominal pain and altered patterns of defecation. This study aims to clarify an increase in the expression and interaction of protein disulfide-isomerase A3 (PDIA3) and Signal Transducer and Activator of Transcription 3 (STAT3) within the membrane of dendritic cells (DCs) from individuals with IBS. Mechanistically, the heightened interaction between PDIA3 and STAT3 at the DC membrane results in reduced translocation of phosphorylated STAT3 (p-STAT3) into the nucleus. The reduction of p-STAT3 to nuclear transport subsequently increased the levels of cathepsin S (CTSS) and major histocompatibility complex class II (MHC-II). Consequently, activated DCs promote CD4+ T cell proliferation and cytokine secretion, including interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-9 (IL-9), and tumour necrosis factor-alpha (TNF-α), thereby contributing to the development of IBS. Importantly, the downregulation of PDIA3 and the administration of punicalagin (Pun), a crucial active compound found in pomegranate peel, alleviate IBS symptoms in rats, such as increased visceral hypersensitivity and abnormal stool characteristics. Collectively, these findings highlight the involvement of the PDIA3-STAT3 protein complex in IBS, providing a novel perspective on the modulation of immune and inflammatory responses. Additionally, this research advances our understanding of the role and mechanisms of PDIA3 inhibitors, presenting new therapeutic possibilities for managing IBS.
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Affiliation(s)
- Chunyan Weng
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
| | - Jingli Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
| | - Xiao Ying
- Department of Gastroenterology, The First People's Hospital of Yongkang, Jinhua 321300, Zhejiang Province, China
| | - Shaopeng Sun
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
| | - Yue Hu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
| | - Xi Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Chenghai He
- Department of Internal Medicine, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou, Zhejiang Province, China
| | - Bin Lu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
| | - Meng Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
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Pedrosa RMSM, Kros JM, Schrijver B, Berrevoets C, Marques RB, van Eijck CCHJ, Debets R, Leenen PM, Dik WA, Mustafa DM. T lymphocyte-derived IFN-γ facilitates breast cancer cells to pass the blood-brain barrier: An in vitro study corroborating translational data. Heliyon 2024; 10:e36598. [PMID: 39262976 PMCID: PMC11388388 DOI: 10.1016/j.heliyon.2024.e36598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 08/18/2024] [Accepted: 08/19/2024] [Indexed: 09/13/2024] Open
Abstract
The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN-γ pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN-γ receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-γ, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. The CXCL-9,-10,-11/CXCR3 axis, dependent on IFN-γ signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN-γ pathway in the formation of brain metastasis of ER-breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.
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Affiliation(s)
- Rute M S M Pedrosa
- Department of Pathology, The Tumor Immuno-Pathology Laboratory, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Johan M Kros
- Department of Pathology, The Tumor Immuno-Pathology Laboratory, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Benjamin Schrijver
- Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Cor Berrevoets
- Department of Medical Oncology, Laboratory of Tumor Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Rute B Marques
- Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | | | - Reno Debets
- Department of Medical Oncology, Laboratory of Tumor Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - PieterJ M Leenen
- Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Willem A Dik
- Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - DanaA M Mustafa
- Department of Pathology, The Tumor Immuno-Pathology Laboratory, Erasmus University Medical Center, Rotterdam, the Netherlands
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11
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Xu J, Song Y, Ding S, Duan W, Xiang G, Wang Z. Myeloid-derived growth factor and its effects on cardiovascular and metabolic diseases. Cytokine Growth Factor Rev 2024; 76:77-85. [PMID: 38185568 DOI: 10.1016/j.cytogfr.2023.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 12/28/2023] [Indexed: 01/09/2024]
Abstract
Myeloid-derived growth factor (MYDGF) is a paracrine protein produced by bone marrow-derived monocytes and macrophages. Current research shows that it has protective effects on the cardiovascular system, such as repairing heart tissue after myocardial infarction, enhancing cardiomyocyte proliferation, improving cardiac regeneration after myocardial injury, regulating proliferation and survival of endothelial cells, reducing endothelial cell damage, resisting pressure overload-induced heart failure, as well as protecting against atherosclerosis. Furthermore, regarding the metabolic diseases, MYDGF has effects of improving type 2 diabetes mellitus, relieving non-alcoholic fatty liver disease, alleviating glomerular diseases, and resisting osteoporosis. Herein, we will discuss the biology of MYDGF and its effects on cardiovascular and metabolic diseases.
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Affiliation(s)
- Jinling Xu
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China
| | - Yanzhuo Song
- Nanchang University, Nanchang, Jiangxi 330031, China
| | - Sheng Ding
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China
| | - Weizhe Duan
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China
| | - Guangda Xiang
- Department of Endocrinology, General Hospital of Central Theater Command, Wuluo Road 627, Wuhan, Hubei 430070, China.
| | - Zhongjing Wang
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China.
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12
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Wei S, Ju F, Xiao J, Li J, Liu T, Hu Z. Aloperine Alleviates Myocardial Injury Induced by Myocardial Ischemia and Reperfusion by Activating the ERK1/2/β-catenin Signaling Pathway. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07566-0. [PMID: 38416285 DOI: 10.1007/s10557-024-07566-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2024] [Indexed: 02/29/2024]
Abstract
OBJECTIVE Myocardial ischemia/reperfusion (I/R) injury can cause severe cardiac damage. Aloperine is a quinolizidine alkaloid found in the leaves and seeds of Sophora alopecuroides L. It has been recognized that aloperine has organ-protective properties; however, its role in cardioprotection is poorly characterized. This study aimed to evaluate the cardioprotective effects of aloperine against myocardial I/R injury in vivo. METHODS Adult male Sprague‒Dawley rats were randomly divided into sham-operated, control, and aloperine groups. All rats except for the sham-operated rats were subjected to 45 min of myocardial ischemia (by left anterior descending ligation) followed by 3 h of reperfusion. Aloperine (10 mg/kg) was given intravenously at the onset of reperfusion. The cardioprotective effects of aloperine were evaluated by determining infarct size, hemodynamics, histological changes, cardiac biomarkers, and cardiac apoptosis. RESULTS Aloperine limited infarct size; improved hemodynamics; attenuated myocardial I/R-induced histological deterioration; decreased serum LDH, CK-MB, and α-HBDH levels; and inhibited apoptosis after myocardial I/R injury. Moreover, aloperine stimulated the phosphorylation of ventricular ERK1/2, which is a major module of MAPK signaling pathways. Furthermore, aloperine increased the ventricular expression levels of β-catenin. Pharmacological inhibition of ERK1/2 diminished aloperine-induced cardioprotection and blocked ERK1/2/β-catenin signaling. CONCLUSIONS These data support the cardioprotective effect of aloperine against myocardial I/R injury, which is mediated, at least in part, by the ERK1/2/β-catenin signaling pathway.
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Affiliation(s)
- Shichao Wei
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Feng Ju
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Junshen Xiao
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiaxue Li
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ting Liu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhaoyang Hu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Yang Q, Lv Z, Wang M, Kong M, Zhong C, Gao K, Wan X. LATS1/2 loss promote tumor immune evasion in endometrial cancer through downregulating MHC-I expression. J Exp Clin Cancer Res 2024; 43:54. [PMID: 38383447 PMCID: PMC10880206 DOI: 10.1186/s13046-024-02979-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/11/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND LATS1/2 are frequently mutated and down-regulated in endometrial cancer (EC), but the contributions of LATS1/2 in EC progression remains unclear. Impaired antigen presentation due to mutations or downregulation of the major histocompatibility complex class I (MHC-I) has been implicated in tumor immune evasion. Herein, we elucidate the oncogenic role that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I. METHODS The mutation and expression as well as the clinical significance of LATS1/2 in EC was assessed in the TCGA cohort and our sample cohort. CRISPR-Cas9 was used to construct knockout cell lines of LATS1/2 in EC. Differentially expressed genes were analyzed by RNA-seq. The interaction between LATS1/2 and STAT1 was verified using co-immunoprecipitation and GST pull-down assays. Mass spectrometry, in vitro kinase assays, ChIP-qPCR, flow cytometry, immunohistochemistry, immunofluorescence and confocal microscopy were performed to investigate the regulation of LATS1/2 on MHC-I through interaction with and phosphorylate STAT1. The killing effect of activated PBMCs on EC cells were used to monitor anti-tumor activity. RESULTS Here, we demonstrate that LATS1/2 are frequently mutated and down-regulated in EC. Moreover, LATS1/2 loss was found to be associated with a significant down-regulation of MHC-I, independently of the Hippo-YAP pathway. Instead, LATS1/2 were found to directly interact with and phosphorylate STAT1 at Ser727, a crucial transcription factor for MHC-I upregulation in response to interferon-gamma (IFN-γ) signaling, to promote STAT1 accumulating and moving into the nucleus to enhance the transcriptional activation of IRF1/NLRC5 on MHC-I. Additionally, the loss of LATS1/2 was observed to confer increased resistance of EC cells to immune cell-mediated killing and this resistance could be reversed by over-expression of MHC-I. CONCLUSION Our findings indicate that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I, leading to the suppression of infiltrating activated CD8 + T cells and highlight the importance of LATS1/2 in IFN-γ signaling-mediated tumor immune response, suggesting that LATS1/2 is a promising target for immune checkpoint blockade therapy in EC.
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Affiliation(s)
- Qianlan Yang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- Shanghai Key Laboratory of Maternal and Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, China
| | - Zehen Lv
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- Shanghai Key Laboratory of Maternal and Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, China
| | - Mengfei Wang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- Shanghai Key Laboratory of Maternal and Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, China
| | - Mengwen Kong
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- Shanghai Key Laboratory of Maternal and Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, China
| | - Cheng Zhong
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- Shanghai Key Laboratory of Maternal and Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, China
| | - Kun Gao
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
- Shanghai Key Laboratory of Maternal and Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, China.
| | - Xiaoping Wan
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
- Shanghai Key Laboratory of Maternal and Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai, 200092, China.
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Shrestha P, Kandel J, Tayara H, Chong KT. DL-SPhos: Prediction of serine phosphorylation sites using transformer language model. Comput Biol Med 2024; 169:107925. [PMID: 38183701 DOI: 10.1016/j.compbiomed.2024.107925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/21/2023] [Accepted: 01/01/2024] [Indexed: 01/08/2024]
Abstract
Serine phosphorylation plays a pivotal role in the pathogenesis of various cellular processes and diseases. Roughly 81% of human diseases have links to phosphorylation, and an overwhelming 86.4% of protein phosphorylation takes place at serine residues. In eukaryotes, over a quarter of proteins undergo phosphorylation, with more than half implicated in numerous disorders, notably cancer and reproductive system diseases. This study primarily focuses on serine-phosphorylation-driven pathogenesis and the critical role of conserved motif identification. While numerous techniques exist for predicting serine phosphorylation sites, traditional wet lab experiments are resource-intensive. Our paper introduces a cutting-edge deep learning tool for predicting S phosphorylation sites, integrating explainable AI for motif identification, a transformer language model, and deep neural network components. We trained our model on protein sequences from UniProt, validated it against the dbPTM benchmark dataset, and employed the PTMD dataset to explore motifs related to mammalian disorders. Our results highlight that our model surpasses other deep learning predictors by a significant 3%. Furthermore, we utilized the local interpretable model-agnostic explanations (LIME) approach to shed light on the predictions, emphasizing the amino acid residues crucial for S phosphorylation. Notably, our model also outperformed competitors in kinase-specific serine phosphorylation prediction on benchmark datasets.
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Affiliation(s)
- Palistha Shrestha
- Department of Electronics and Information Engineering, Jeonbuk National University, Jeonju-si, 54896, Jeollabuk-do, Republic of Korea
| | - Jeevan Kandel
- Graduate School of Integrated Energy-AI, Jeonbuk National University, Jeonju-si, 54896, Jeollabuk-do, Republic of Korea
| | - Hilal Tayara
- School of International Engineering and Science, Jeonbuk National University, Jeonju-si, 54896, Jeollabuk-do, Republic of Korea.
| | - Kil To Chong
- Department of Electronics and Information Engineering, Jeonbuk National University, Jeonju-si, 54896, Jeollabuk-do, Republic of Korea; Advances Electronics and Information Research Center, Jeonbuk National University, Jeonju-si, 54896, Jeollabuk-do, Republic of Korea.
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15
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Qu JH, Chakir K, Tarasov KV, Riordon DR, Perino MG, Silvester AJ, Lakatta EG. Reprogramming of cardiac phosphoproteome, proteome, and transcriptome confers resilience to chronic adenylyl cyclase-driven stress. eLife 2024; 12:RP88732. [PMID: 38251682 PMCID: PMC10945681 DOI: 10.7554/elife.88732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2024] Open
Abstract
Our prior study (Tarasov et al., 2022) discovered that numerous adaptive mechanisms emerge in response to cardiac-specific overexpression of adenylyl cyclase type 8 (TGAC8) which included overexpression of a large number of proteins. Here, we conducted an unbiased phosphoproteomics analysis in order to determine the role of altered protein phosphorylation in the adaptive heart performance and protection profile of adult TGAC8 left ventricle (LV) at 3-4 months of age, and integrated the phosphoproteome with transcriptome and proteome. Based on differentially regulated phosphoproteins by genotype, numerous stress-response pathways within reprogrammed TGAC8 LV, including PKA, PI3K, and AMPK signaling pathways, predicted upstream regulators (e.g. PDPK1, PAK1, and PTK2B), and downstream functions (e.g. cell viability, protein quality control), and metabolism were enriched. In addition to PKA, numerous other kinases and phosphatases were hyper-phosphorylated in TGAC8 vs. WT. Hyper-phosphorylated transcriptional factors in TGAC8 were associated with increased mRNA transcription, immune responses, and metabolic pathways. Combination of the phosphoproteome with its proteome and with the previously published TGAC8 transcriptome enabled the elucidation of cardiac performance and adaptive protection profiles coordinately regulated at post-translational modification (PTM) (phosphorylation), translational, and transcriptional levels. Many stress-response signaling pathways, i.e., PI3K/AKT, ERK/MAPK, and ubiquitin labeling, were consistently enriched and activated in the TGAC8 LV at transcriptional, translational, and PTM levels. Thus, reprogramming of the cardiac phosphoproteome, proteome, and transcriptome confers resilience to chronic adenylyl cyclase-driven stress. We identified numerous pathways/function predictions via gene sets, phosphopeptides, and phosphoproteins, which may point to potential novel therapeutic targets to enhance heart adaptivity, maintaining heart performance while avoiding cardiac dysfunction.
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Affiliation(s)
- Jia-Hua Qu
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
- Department of Immunology, St. Jude Children’s Research HospitalMemphisUnited States
| | - Khalid Chakir
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Kirill V Tarasov
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Daniel R Riordon
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Maria Grazia Perino
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Allwin Jennifa Silvester
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
| | - Edward G Lakatta
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of HealthBaltimoreUnited States
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16
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Sakata T, Kohno H, Inui T, Ikeuchi H, Shiko Y, Kawasaki Y, Suzuki S, Tanaka S, Obana M, Ishikawa K, Fujio Y, Matsumiya G. Cardioprotective effect of Interleukin-11 against warm ischemia-reperfusion injury in a rat heart donor model. Eur J Pharmacol 2023; 961:176145. [PMID: 37923160 DOI: 10.1016/j.ejphar.2023.176145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 10/08/2023] [Accepted: 10/19/2023] [Indexed: 11/07/2023]
Abstract
Shortage of donor organs for heart transplantation is a worldwide problem. Donation after circulatory death (DCD) has been proposed to expand the donor pool. However, in contrast to the donation after brain death that undergoes immediate cold preservation, warm ischemia and subsequent reperfusion injury are inevitable in DCD. It has been reported that interleukin-11 (IL-11) mitigates ischemia-reperfusion injury in rodent models of myocardial infarction and donation after brain death heart transplantation. We hypothesized that IL-11 also offers benefit to warm ischemia in an experimental model of cardiac transplantation that resembles DCD. The hearts of naïve male Sprague Dawley rats (n = 15/group) were procured, subjected to 25-min warm ischemia, and reperfused for 60 min using Langendorff apparatus. IL-11 or saline was administered intravenously before the procurement, added to maintenance buffer, and infused via perfusion during reperfusion. IL-11 group exhibited significantly better cardiac function post-reperfusion. Severely damaged mitochondria was found in the electron microscopic analysis of control hearts whereas the mitochondrial structure was better preserved in the IL-11 treated hearts. Immunoblot analysis using neonatal rat cardiomyocytes revealed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation at Ser727 after IL-11 treatment, suggesting its role in mitochondrial protection. Consistent with expected activation of mitochondrial respiration by mitochondrial STAT3, immunohistochemical staining demonstrated a higher mitochondrial cytochrome c oxidase subunit 2 expression. In summary, IL-11 protects the heart from warm ischemia reperfusion injury by alleviating mitochondrial injury and could be a viable therapeutic option for DCD heart transplantation.
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Affiliation(s)
- Tomoki Sakata
- Department of Cardiovascular Surgery, Chiba University Hospital, Chiba, Japan; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
| | - Hiroki Kohno
- Department of Cardiovascular Surgery, Chiba University Hospital, Chiba, Japan
| | - Tomohiko Inui
- Department of Cardiovascular Surgery, Chiba University Hospital, Chiba, Japan
| | - Hiroki Ikeuchi
- Department of Cardiovascular Surgery, Chiba University Hospital, Chiba, Japan
| | - Yuki Shiko
- Biostatistics Section, Clinical Research Center, Chiba University Hospital, Chiba, Japan
| | - Yohei Kawasaki
- Faculty of Nursing, Japanese Red Cross College of Nursing, Tokyo, Japan
| | - Shota Suzuki
- Laboratory of Clinical Science and Biomedicine, Osaka University Graduate School of Pharmaceutical Sciences, Osaka, Japan
| | - Shota Tanaka
- Laboratory of Clinical Science and Biomedicine, Osaka University Graduate School of Pharmaceutical Sciences, Osaka, Japan
| | - Masanori Obana
- Laboratory of Clinical Science and Biomedicine, Osaka University Graduate School of Pharmaceutical Sciences, Osaka, Japan
| | - Kiyotake Ishikawa
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Yasushi Fujio
- Laboratory of Clinical Science and Biomedicine, Osaka University Graduate School of Pharmaceutical Sciences, Osaka, Japan
| | - Goro Matsumiya
- Department of Cardiovascular Surgery, Chiba University Hospital, Chiba, Japan
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Mahjoor M, Mahmoudvand G, Farokhi S, Shadab A, Kashfi M, Afkhami H. Double-edged sword of JAK/STAT signaling pathway in viral infections: novel insights into virotherapy. Cell Commun Signal 2023; 21:272. [PMID: 37784164 PMCID: PMC10544547 DOI: 10.1186/s12964-023-01240-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/19/2023] [Indexed: 10/04/2023] Open
Abstract
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) is an intricate signaling cascade composed of various cytokines, interferons (IFN, growth factors, and other molecules. This pathway provides a delicate mechanism through which extracellular factors adjust gene expression, thereby acting as a substantial basis for environmental signals to influence cell growth and differentiation. The interactions between the JAK/STAT cascade and antiviral IFNs are critical to the host's immune response against viral microorganisms. Recently, with the emergence of therapeutic classes that target JAKs, the significance of this cascade has been recognized in an unprecedented way. Despite the functions of the JAK/STAT pathway in adjusting immune responses against viral pathogens, a vast body of evidence proposes the role of this cascade in the replication and pathogenesis of viral pathogens. In this article, we review the structure of the JAK/STAT signaling cascade and its role in immuno-inflammatory responses. We also highlight the paradoxical effects of this pathway in the pathogenesis of viral infections. Video Abstract.
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Affiliation(s)
- Mohamad Mahjoor
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Golnaz Mahmoudvand
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Simin Farokhi
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Alireza Shadab
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
- Iran University of Medical Sciences, Deputy of Health, Tehran, Iran
| | - Mojtaba Kashfi
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
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18
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Rao SS, Nelson PA, Lunde HS, Haugland GT. Evolutionary, comparative, and functional analyses of STATs and regulation of the JAK-STAT pathway in lumpfish upon bacterial and poly(I:C) exposure. Front Cell Infect Microbiol 2023; 13:1252744. [PMID: 37808912 PMCID: PMC10556531 DOI: 10.3389/fcimb.2023.1252744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/05/2023] [Indexed: 10/10/2023] Open
Abstract
Background The Janus kinase/signal transducers and activators of transcription (JAK-STAT) system regulates several biological processes by affecting transcription of genes as a response to cytokines and growth factors. In the present study, we have characterized the STAT genes in lumpfish (Cyclopterus lumpus L.), belonging to the order Perciformes, and investigated regulation of the JAK-STAT signaling pathway upon exposure to bacteria (Vibrio anguillarum) and poly(I:C), the latter mimicking antiviral responses. Methods Characterization and evolutionary analyses of the STATs were performed by phylogeny, protein domain, homology similarity and synteny analyses. Antibacterial and antiviral responses were investigated by performing KEGG pathway analysis. Results We observed that lumpfish have stat1a, 2, 3, 4, 5a, 5b, and 6. Transcriptome-wide analyses showed that most components of the JAK-STAT pathway were present in lumpfish. il-6, il-10, il-21, iκBα and stat3 were upregulated 6 hours post exposure (hpe) against bacteria while type I interferons (IFNs), irf1, irf3, irf10, stat1 and 2 were upregulated 24 hpe against poly(I:C). Conclusions Our findings shed light on the diversity and evolution of the STATs and the data show that the STAT genes are highly conserved among fish, including lumpfish. The transcriptome-wide analyses lay the groundwork for future research into the functional significance of these genes in regulating critical biological processes and make an important basis for development of prophylactic measure such as vaccination, which is highly needed for lumpfish since it is vulnerable for both bacterial and viral diseases.
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Affiliation(s)
- Shreesha S Rao
- Department of Biological Sciences, Bergen High-Technology Centre, University of Bergen, Bergen, Norway
| | - Patrick A Nelson
- Department of Biological Sciences, Bergen High-Technology Centre, University of Bergen, Bergen, Norway
| | - Harald S Lunde
- Department of Biological Sciences, Bergen High-Technology Centre, University of Bergen, Bergen, Norway
| | - Gyri T Haugland
- Department of Biological Sciences, Bergen High-Technology Centre, University of Bergen, Bergen, Norway
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Napier M, Reynolds K, Scott AL. Glial-mediated dysregulation of neurodevelopment in Fragile X Syndrome. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 173:187-215. [PMID: 37993178 DOI: 10.1016/bs.irn.2023.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
Astrocytes are highly involved in a multitude of developmental processes that are known to be dysregulated in Fragile X Syndrome. Here, we examine these processes individually and review the roles astrocytes play in contributing to the pathology of this syndrome. As a growing area of interest in the field, new and exciting insight is continually emerging. Understanding these glial-mediated roles is imperative for elucidating the underlying molecular mechanisms at play, not only in Fragile X Syndrome, but also other ASD-related disorders. Understanding these roles will be central to the future development of effective, clinically-relevant treatments of these disorders.
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Affiliation(s)
- M Napier
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - K Reynolds
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Department of Neuroscience, Tufts University School of Medicine, Boston, United States
| | - A L Scott
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
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20
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Faida P, Attiogbe MKI, Majeed U, Zhao J, Qu L, Fan D. Lung cancer treatment potential and limits associated with the STAT family of transcription factors. Cell Signal 2023:110797. [PMID: 37423343 DOI: 10.1016/j.cellsig.2023.110797] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/19/2023] [Accepted: 07/04/2023] [Indexed: 07/11/2023]
Abstract
Lung cancer is one of the mortal cancers and the leading cause of cancer-related mortality, with a cancer survival rate of fewer than 5% in developing nations. This low survival rate can be linked to things like late-stage detection, quick postoperative recurrences in patients receiving therapy, and chemoresistance developing against various lung cancer treatments. Signal transducer and activator of transcription (STAT) family of transcription factors are involved in lung cancer cell proliferation, metastasis, immunological control, and treatment resistance. By interacting with specific DNA sequences, STAT proteins trigger the production of particular genes, which in turn result in adaptive and incredibly specific biological responses. In the human genome, seven STAT proteins have been discovered (STAT1 to STAT6, including STAT5a and STAT5b). Many external signaling proteins can activate unphosphorylated STATs (uSTATs), which are found inactively in the cytoplasm. When STAT proteins are activated, they can increase the transcription of several target genes, which leads to unchecked cellular proliferation, anti-apoptotic reactions, and angiogenesis. The effects of STAT transcription factors on lung cancer are variable; some are either pro- or anti-tumorigenic, while others maintain dual, context-dependent activities. Here, we give a succinct summary of the various functions that each member of the STAT family plays in lung cancer and go into more detail about the advantages and disadvantages of pharmacologically targeting STAT proteins and their upstream activators in the context of lung cancer treatment.
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Affiliation(s)
- Paison Faida
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Mawusse K I Attiogbe
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Usman Majeed
- College of Food Science and Technology, Northwest University, Xi'an, Shaanxi 710069, China
| | - Jing Zhao
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Linlin Qu
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China.
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21
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Park JS, Perl A. Endosome Traffic Modulates Pro-Inflammatory Signal Transduction in CD4 + T Cells-Implications for the Pathogenesis of Systemic Lupus Erythematosus. Int J Mol Sci 2023; 24:10749. [PMID: 37445926 DOI: 10.3390/ijms241310749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/10/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Endocytic recycling regulates the cell surface receptor composition of the plasma membrane. The surface expression levels of the T cell receptor (TCR), in concert with signal transducing co-receptors, regulate T cell responses, such as proliferation, differentiation, and cytokine production. Altered TCR expression contributes to pro-inflammatory skewing, which is a hallmark of autoimmune diseases, such as systemic lupus erythematosus (SLE), defined by a reduced function of regulatory T cells (Tregs) and the expansion of CD4+ helper T (Th) cells. The ensuing secretion of inflammatory cytokines, such as interferon-γ and interleukin (IL)-4, IL-17, IL-21, and IL-23, trigger autoantibody production and tissue infiltration by cells of the adaptive and innate immune system that induce organ damage. Endocytic recycling influences immunological synapse formation by CD4+ T lymphocytes, signal transduction from crosslinked surface receptors through recruitment of adaptor molecules, intracellular traffic of organelles, and the generation of metabolites to support growth, cytokine production, and epigenetic control of DNA replication and gene expression in the cell nucleus. This review will delineate checkpoints of endosome traffic that can be targeted for therapeutic interventions in autoimmune and other disease conditions.
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Affiliation(s)
- Joy S Park
- Department of Medicine, Norton College of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA
- Department of Biochemistry and Molecular Biology, Norton College of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA
| | - Andras Perl
- Department of Medicine, Norton College of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA
- Department of Biochemistry and Molecular Biology, Norton College of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA
- Department of Microbiology and Immunology, Norton College of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA
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22
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Xu J, Zhang B, Cai J, Peng Q, Hu J, Askar P, Shangguan J, Su W, Zhu C, Sun H, Zhou S, Chen G, Yang X, Gu Y. The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration. Mol Med 2023; 29:79. [PMID: 37365519 DOI: 10.1186/s10020-023-00667-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 05/21/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. METHODS By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. RESULTS Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. CONCLUSION Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases.
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Affiliation(s)
- Jinghui Xu
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Bin Zhang
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Jieyi Cai
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Qianqian Peng
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Junxia Hu
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Parizat Askar
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Jianghong Shangguan
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Wenfeng Su
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Changlai Zhu
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Hualin Sun
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Songlin Zhou
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Gang Chen
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China
| | - Xiaoming Yang
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
| | - Yun Gu
- Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.
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23
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Cheung CCL, Seah YHJ, Fang J, Orpilla NHC, Lau MC, Lim CJ, Lim X, Lee JNLW, Lim JCT, Lim S, Cheng Q, Toh HC, Choo SP, Lee SY, Lee JJX, Liu J, Lim TKH, Tai D, Yeong J. Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma. Front Immunol 2023; 14:1150985. [PMID: 37342338 PMCID: PMC10277502 DOI: 10.3389/fimmu.2023.1150985] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 05/04/2023] [Indexed: 06/22/2023] Open
Abstract
Introduction Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. Methods HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. Results Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status. Conclusion Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.
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Affiliation(s)
- Chun Chau Lawrence Cheung
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Yong Hock Justin Seah
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Juntao Fang
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Mai Chan Lau
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Chun Jye Lim
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Xinru Lim
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Justina Nadia Li Wen Lee
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Jeffrey Chun Tatt Lim
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Sherlly Lim
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Qing Cheng
- Duke-NUS Medical School, Singapore, Singapore
- Center of Statistical Research, School of Statistics, Southwestern University of Finance and Economics, Chengdu, Sichuan, China
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Su Pin Choo
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Suat Ying Lee
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joycelyn Jie Xin Lee
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Jin Liu
- Duke-NUS Medical School, Singapore, Singapore
| | - Tony Kiat Hon Lim
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - David Tai
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joe Yeong
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
- Singapore Immunology Network (SIgN), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
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24
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Huang X, Winter D, Glover DJ, Supuran CT, Donald WA. Effects of Phosphorylation on the Activity, Inhibition and Stability of Carbonic Anhydrases. Int J Mol Sci 2023; 24:ijms24119275. [PMID: 37298228 DOI: 10.3390/ijms24119275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Carbonic anhydrases (CAs) are a metalloenzyme family that have important roles in cellular processes including pH homeostasis and have been implicated in multiple pathological conditions. Small molecule inhibitors have been developed to target carbonic anhydrases, but the effects of post-translational modifications (PTMs) on the activity and inhibition profiles of these enzymes remain unclear. Here, we investigate the effects of phosphorylation, the most prevalent carbonic anhydrase PTM, on the activities and drug-binding affinities of human CAI and CAII, two heavily modified active isozymes. Using serine to glutamic acid (S > E) mutations to mimic the effect of phosphorylation, we demonstrate that phosphomimics at a single site can significantly increase or decrease the catalytic efficiencies of CAs, depending on both the position of the modification and the CA isoform. We also show that the S > E mutation at Ser50 of hCAII decreases the binding affinities of hCAII with well-characterized sulphonamide inhibitors including by over 800-fold for acetazolamide. Our findings suggest that CA phosphorylation may serve as a regulatory mechanism for enzymatic activity, and affect the binding affinity and specificity of small, drug and drug-like molecules. This work should motivate future studies examining the PTM-modification forms of CAs and their distributions, which should provide insights into CA physiopathological functions and facilitate the development of 'modform-specific' carbonic anhydrase inhibitors.
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Affiliation(s)
- Xiaojing Huang
- School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
| | - Daniel Winter
- School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
| | - Dominic J Glover
- School of Biotechnology & Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Claudiu T Supuran
- Neurofarba Department, Sezione di Scienze Farmaceutiche, Universita degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
| | - William A Donald
- School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
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25
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Shamir I, Tsarfaty I, Paret G, Nevo-Caspi Y. Differential silencing of STAT3 isoforms leads to changes in STAT3 activation. Oncotarget 2023; 14:366-376. [PMID: 37097001 DOI: 10.18632/oncotarget.28412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in multiple fundamental biological processes and a key player in cancer development and progression. STAT3 is activated upon tyrosine phosphorylation and is constitutively active in various malignancies; therefore, the expression of pSTAT3 has been recognized as a predictor of poor survival. STAT3 encodes two alternatively-spliced STAT3 isoforms: the full-length STAT3α isoform and the truncated STAT3β isoform. These isoforms have been suggested as the reason for the occasionally observed opposing roles of STAT3 in cancer: an oncogene, on one hand, and a tumor suppressor on the other. To investigate their roles in aggressive breast cancer, we separately silenced each isoform and found that they affect each other's activation, impacting cell viability, cytokine expression, and migration. Silencing specific isoforms can lead to a more favorable balance of activated STAT3 proteins in the cell. Distinguishing between the two isoforms and their active forms is crucial for STAT3-related cancer diagnosis and therapy.
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Affiliation(s)
- Inbal Shamir
- Department of Pediatric Critical Care Medicine, Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel
| | - Ilan Tsarfaty
- Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gidi Paret
- Department of Pediatric Critical Care Medicine, Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel
| | - Yael Nevo-Caspi
- Department of Pediatric Critical Care Medicine, Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel
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26
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Palakurthi B, Fross SR, Guldner IH, Aleksandrovic E, Liu X, Martino AK, Wang Q, Neff RA, Golomb SM, Lewis C, Peng Y, Howe EN, Zhang S. Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer. Nat Commun 2023; 14:2109. [PMID: 37055410 PMCID: PMC10101955 DOI: 10.1038/s41467-023-37727-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/27/2023] [Indexed: 04/15/2023] Open
Abstract
Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1's role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.
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Affiliation(s)
- Bhavana Palakurthi
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
- Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA
| | - Shaneann R Fross
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
- Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA
| | - Ian H Guldner
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
- Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA
| | - Emilija Aleksandrovic
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
- Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA
| | - Xiyu Liu
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
- Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA
| | - Anna K Martino
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
| | - Qingfei Wang
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
- Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA
| | - Ryan A Neff
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
| | - Samantha M Golomb
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
- Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA
| | - Cheryl Lewis
- Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA
| | - Yan Peng
- Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA
| | - Erin N Howe
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA
- Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA
| | - Siyuan Zhang
- Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, 46556, USA.
- Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN, 46617, USA.
- Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA.
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27
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Luo W, Conter L, Elsner RA, Smita S, Weisel F, Callahan D, Wu S, Chikina M, Shlomchik M. IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells. Sci Immunol 2023; 8:eadd1823. [PMID: 36800413 PMCID: PMC10206726 DOI: 10.1126/sciimmunol.add1823] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 01/26/2023] [Indexed: 02/19/2023]
Abstract
Both B cell receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to synergistically induce c-MYC and phosphorylated S6 ribosomal protein (p-S6), markers of positive selection. How interleukin-21 (IL-21), a key T follicular helper (TFH)-derived cytokine, affects GCBCs is unclear. Like BCR and CD40 signals, IL-21 receptor (IL-21R) plus CD40 signals also synergize to induce c-MYC and p-S6 in GCBCs. However, IL-21R plus CD40 stimulation differentially affects GCBC fate compared with BCR plus CD40 ligation-engaging unique molecular mechanisms-as revealed by bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry of GCBCs in vitro and in vivo. Whereas both signal pairs induced BLIMP1 in some GCBCs, only the IL-21R/CD40 combination induced IRF4hi/CD138+ cells, indicative of plasma cell differentiation, along with CCR6+/CD38+ memory B cell precursors. These findings reveal a second positive selection pathway in GCBCs, document rewired IL-21R signaling in GCBCs, and link specific TFH- and Ag-derived signals to GCBC differentiation.
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Affiliation(s)
- Wei Luo
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- These authors contributed equally
- Present address: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Laura Conter
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- These authors contributed equally
| | - Rebecca A. Elsner
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- These authors contributed equally
| | - Shuchi Smita
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Florian Weisel
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Derrick Callahan
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Shuxian Wu
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Maria Chikina
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Mark Shlomchik
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Lead contact
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Liu J, Wang F, Luo F. The Role of JAK/STAT Pathway in Fibrotic Diseases: Molecular and Cellular Mechanisms. Biomolecules 2023; 13:biom13010119. [PMID: 36671504 PMCID: PMC9855819 DOI: 10.3390/biom13010119] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/25/2022] [Accepted: 12/27/2022] [Indexed: 01/11/2023] Open
Abstract
There are four members of the JAK family and seven of the STAT family in mammals. The JAK/STAT molecular pathway could be activated by broad hormones, cytokines, growth factors, and more. The JAK/STAT signaling pathway extensively mediates various biological processes such as cell proliferation, differentiation, migration, apoptosis, and immune regulation. JAK/STAT activation is closely related to growth and development, homeostasis, various solid tumors, inflammatory illness, and autoimmune diseases. Recently, with the deepening understanding of the JAK/STAT pathway, the relationship between JAK/STAT and the pathophysiology of fibrotic diseases was noticed, including the liver, renal, heart, bone marrow, and lung. JAK inhibitor has been approved for myelofibrosis, and subsequently, JAK/STAT may serve as a promising target for fibrosis in other organs. Therefore, this article reviews the roles and mechanisms of the JAK/STAT signaling pathway in fibrotic diseases.
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Affiliation(s)
- Jia Liu
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Faping Wang
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Fengming Luo
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
- Correspondence: ; Tel.: +86-18980601355
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Wong GL, Manore SG, Doheny DL, Lo HW. STAT family of transcription factors in breast cancer: Pathogenesis and therapeutic opportunities and challenges. Semin Cancer Biol 2022; 86:84-106. [PMID: 35995341 PMCID: PMC9714692 DOI: 10.1016/j.semcancer.2022.08.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most commonly diagnosed cancer and second-leading cause of cancer deaths in women. Breast cancer stem cells (BCSCs) promote metastasis and therapeutic resistance contributing to tumor relapse. Through activating genes important for BCSCs, transcription factors contribute to breast cancer metastasis and therapeutic resistance, including the signal transducer and activator of transcription (STAT) family of transcription factors. The STAT family consists of six major isoforms, STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6. Canonical STAT signaling is activated by the binding of an extracellular ligand to a cell-surface receptor followed by STAT phosphorylation, leading to STAT nuclear translocation and transactivation of target genes. It is important to note that STAT transcription factors exhibit diverse effects in breast cancer; some are either pro- or anti-tumorigenic while others maintain dual, context-dependent roles. Among the STAT transcription factors, STAT3 is the most widely studied STAT protein in breast cancer for its critical roles in promoting BCSCs, breast cancer cell proliferation, invasion, angiogenesis, metastasis, and immune evasion. Consequently, there have been substantial efforts in developing cancer therapeutics to target breast cancer with dysregulated STAT3 signaling. In this comprehensive review, we will summarize the diverse roles that each STAT family member plays in breast cancer pathobiology, as well as, the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators in the context of breast cancer treatment.
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Affiliation(s)
- Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Daniel L Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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Li Y, He X, Lu X, Gong Z, Li Q, Zhang L, Yang R, Wu C, Huang J, Ding J, He Y, Liu W, Chen C, Cao B, Zhou D, Shi Y, Chen J, Wang C, Zhang S, Zhang J, Ye J, You H. METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions. Nat Commun 2022; 13:6350. [PMID: 36289222 PMCID: PMC9605963 DOI: 10.1038/s41467-022-34209-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 10/14/2022] [Indexed: 12/25/2022] Open
Abstract
The methyltransferase like 3 (METTL3) has been generally recognized as a nuclear protein bearing oncogenic properties. We find predominantly cytoplasmic METTL3 expression inversely correlates with node metastasis in human cancers. It remains unclear if nuclear METTL3 is functionally distinct from cytosolic METTL3 in driving tumorigenesis and, if any, how tumor cells sense oncogenic insults to coordinate METTL3 functions within these intracellular compartments. Here, we report an acetylation-dependent regulation of METTL3 localization that impacts on metastatic dissemination. We identify an IL-6-dependent positive feedback axis to facilitate nuclear METTL3 functions, eliciting breast cancer metastasis. IL-6, whose mRNA transcript is subjected to METTL3-mediated m6A modification, promotes METTL3 deacetylation and nuclear translocation, thereby inducing global m6A abundance. This deacetylation-mediated nuclear shift of METTL3 can be counterbalanced by SIRT1 inhibition, a process that is further enforced by aspirin treatment, leading to ablated lung metastasis via impaired m6A methylation. Intriguingly, acetylation-mimetic METTL3 mutant reconstitution results in enhanced translation and compromised metastatic potential. Our study identifies an acetylation-dependent regulatory mechanism determining the subcellular localization of METTL3, which may provide mechanistic clues for developing therapeutic strategies to combat breast cancer metastasis.
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Affiliation(s)
- Yuanpei Li
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China
| | - Xiaoniu He
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China
| | - Xiao Lu
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China
| | - Zhicheng Gong
- grid.459328.10000 0004 1758 9149Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, 214062 Wuxi, China
| | - Qing Li
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China
| | - Lei Zhang
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China
| | - Ronghui Yang
- grid.24696.3f0000 0004 0369 153XDepartment of Biochemistry and Molecular Biology, Capital Medical University, 100069 Beijing, China
| | - Chengyi Wu
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China
| | - Jialiang Huang
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China
| | - Jiancheng Ding
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, 361102 Xiamen, China
| | - Yaohui He
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, 361102 Xiamen, China
| | - Wen Liu
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, 361102 Xiamen, China
| | - Ceshi Chen
- grid.9227.e0000000119573309Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223 Kunming, China
| | - Bin Cao
- grid.12955.3a0000 0001 2264 7233Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, 361102 Xiamen, China
| | - Dawang Zhou
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China
| | - Yufeng Shi
- grid.24516.340000000123704535Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, 200092 Shanghai, China
| | - Juxiang Chen
- grid.73113.370000 0004 0369 1660Department of Neurosurgery, Shanghai Changhai Hospital, Naval Medical University, 200433 Shanghai, China
| | - Chuangui Wang
- grid.412509.b0000 0004 1808 3414The Biomedical Translational Research Institute, School of Life Sciences, Shandong University of Technology, 255049 Zibo, China
| | - Shengping Zhang
- grid.16821.3c0000 0004 0368 8293Translational Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620 Shanghai, China
| | - Jian Zhang
- grid.233520.50000 0004 1761 4404The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi’an, China
| | - Jing Ye
- grid.233520.50000 0004 1761 4404Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032 Xi’an, China
| | - Han You
- grid.12955.3a0000 0001 2264 7233State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102 Xiamen, China
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Davis CM, Lyon-Scott K, Varlamov EV, Zhang WH, Alkayed NJ. Role of Endothelial STAT3 in Cerebrovascular Function and Protection from Ischemic Brain Injury. Int J Mol Sci 2022; 23:12167. [PMID: 36293020 PMCID: PMC9602684 DOI: 10.3390/ijms232012167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 10/04/2022] [Accepted: 10/08/2022] [Indexed: 02/25/2024] Open
Abstract
STAT3 plays a protective role against ischemic brain injury; however, it is not clear which brain cell type mediates this effect, and by which mechanism. We tested the hypothesis that endothelial STAT3 contributes to protection from cerebral ischemia, by preserving cerebrovascular endothelial function and blood-brain barrier (BBB) integrity. The objective of this study was to determine the role of STAT3 in cerebrovascular endothelial cell (EC) survival and function, and its role in tissue outcome after cerebral ischemia. We found that in primary mouse brain microvascular ECs, STAT3 was constitutively active, and its phosphorylation was reduced by oxygen-glucose deprivation (OGD), recovering after re-oxygenation. STAT3 inhibition, using two mechanistically different pharmacological inhibitors, increased EC injury after OGD. The sub-lethal inhibition of STAT3 caused endothelial dysfunction, demonstrated by reduced nitric oxide release in response to acetylcholine and reduced barrier function of the endothelial monolayer. Finally, mice with reduced endothelial STAT3 (Tie2-Cre; STAT3flox/wt) sustained larger brain infarcts after middle cerebral artery occlusion (MCAO) compared to wild-type (WT) littermates. We conclude that STAT3 is vital to maintaining cerebrovascular integrity, playing a role in EC survival and function, and protection against cerebral ischemia. Endothelial STAT3 may serve as a potential target in preventing endothelial dysfunction after stroke.
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Affiliation(s)
- Catherine M. Davis
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, 3181 S.W. Sam Jackson Pk. Rd., UHN-2, Portland, OR 97239-3098, USA
| | - Kristin Lyon-Scott
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, 3181 S.W. Sam Jackson Pk. Rd., UHN-2, Portland, OR 97239-3098, USA
| | - Elena V. Varlamov
- Department of Medicine, Division of Endocrinology and Department of Neurological Surgery, Oregon Health & Science University, 3181 S.W. Sam Jackson Pk. Rd., UHN-2, Portland, OR 97239-3098, USA
| | - Wenri H. Zhang
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, 3181 S.W. Sam Jackson Pk. Rd., UHN-2, Portland, OR 97239-3098, USA
| | - Nabil J. Alkayed
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, 3181 S.W. Sam Jackson Pk. Rd., UHN-2, Portland, OR 97239-3098, USA
- The Knight Cardiovascular Institute, Oregon Health & Science University, 3181 S.W. Sam Jackson Pk. Rd., UHN-2, Portland, OR 97239-3098, USA
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Ramana CV. Insights into functional connectivity in mammalian signal transduction pathways by pairwise comparison of protein interaction partners of critical signaling hubs. Biomol Concepts 2022; 13:298-313. [DOI: 10.1515/bmc-2022-0023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/09/2022] [Indexed: 11/15/2022] Open
Abstract
Abstract
Growth factors and cytokines activate signal transduction pathways and regulate gene expression in eukaryotes. Intracellular domains of activated receptors recruit several protein kinases as well as transcription factors that serve as platforms or hubs for the assembly of multi-protein complexes. The signaling hubs involved in a related biologic function often share common interaction proteins and target genes. This functional connectivity suggests that a pairwise comparison of protein interaction partners of signaling hubs and network analysis of common partners and their expression analysis might lead to the identification of critical nodes in cellular signaling. A pairwise comparison of signaling hubs across several related pathways might reveal novel signaling modules. Analysis of protein interaction connectome by Venn (PIC-Venn) of transcription factors STAT1, STAT3, NFKB1, RELA, FOS, and JUN, and their common interaction network suggested that BRCA1 and TSC22D3 function as critical nodes in immune responses by connecting the signaling hubs into signaling modules. Transcriptional regulation of critical hubs may play a major role in the lung epithelial cells in response to SARS-CoV-2 and in COVID-19 patients. Mutations and differential expression levels of these critical nodes and modules in pathological conditions might deregulate signaling pathways and their target genes involved in inflammation. Biological connectivity emerges from the structural connectivity of interaction networks across several signaling hubs in related pathways. The main objectives of this study are to identify critical hubs, critical nodes, and modules involved in the signal transduction pathways of innate and adaptive immunity. Application of PIC-Venn to several signaling hubs might reveal novel nodes and modules that can be targeted by small regulatory molecules to simultaneously activate or inhibit cell signaling in health and disease.
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Affiliation(s)
- Chilakamarti V. Ramana
- Department of Experimental Therapeutics, Thoreau Laboratory for Global Health, University of Massachusetts , Lowell , MA 01854 , USA
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33
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Wu JY, Xie JH, Chen YJ, Fu XQ, Wang RJ, Deng YY, Wang S, Yu HX, Liang C, Yu ZL. Amelioration of TPA-induced skin inflammation by the leaf extract of Vernonia amygdalina involves ERK/STAT3 (Ser727) signaling inhibition. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 102:154194. [PMID: 35660348 DOI: 10.1016/j.phymed.2022.154194] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 05/16/2022] [Accepted: 05/20/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Uncontrolled inflammation causes health problems. Extracellular signal-regulated kinase (ERK) phosphorylates signal transducer and activator of transcription 3 (STAT3) at Ser727, resulting in inflammation. The leaf of Vernonia amygdalina (VA) is a medicinal herb for managing inflammation-associated diseases. Oral administration or topical application of VA leaf extract exerts anti-inflammatory effects in rat models. However, the anti-inflammatory mechanisms of the herb are not fully understood. PURPOSE In this study, we aimed to investigate the involvement of ERK/STAT3 (Ser727) signaling in the anti-inflammatory effects of an ethanolic extract of VA leaves. STUDY DESIGN AND METHODS Extracts of VA leaves were prepared with different concentrations of ethanol. A LPS-stimulated RAW264.7 cell model was used for in vitro assays, and a TPA (12-O-tetradecanoylphorbol-13-acetate)-induced ear edema mouse model was employed for in vivo assays. The 95% ethanol extract of VA leaves (VAE) exerted the strongest inhibitory effect on nitric oxide (NO) production in LPS-stimulated macrophages; thus it was selected for use in this study. Hematoxylin and eosin (H&E) staining was used to examine pathological conditions of mouse ear tissues. Griess reagent was employed to examine NO generation in cell cultures. Immunoblotting and ELISA were used to examine protein levels, and RT-qPCR was employed to examine mRNA levels. RESULTS Topical application of VAE ameliorated mouse ear edema induced by TPA. VAE suppressed the phosphorylation of ERK (Thr202/Tyr204) and STAT3 (Ser727); and decreased protein levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) in the mouse ear tissues and in LPS-stimulated RAW 264.7 cells. VAE also inhibited NO production, and lowered mRNA levels of IL-6, IL-1β and TNF-α in the macrophages. CONCLUSIONS VAE ameliorates TPA-induced mouse ear edema. Suppression of ERK/STAT3 (Ser727) signaling is involved in VAE's anti-inflammatory effects. These novel data provide further pharmacological justifications for the medicinal use of VA in treating inflammation-associated diseases, and lay the groundwork for developing VAE into a new anti-inflammatory agent.
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Key Words
- Acute inflammation
- COX-2, cyclooxygenase-2
- ERK
- ERK, extracellular signal-regulated kinase
- IL, interleukin
- MAPK, mitogen-activated protein kinase
- NO, nitric oxide
- STAT3
- STAT3, signal transducer and activator of transcription 3
- TNF-α, tumor necrosis factor-α
- TPA
- VA, Vernonia amygdalina Del.
- VAE, the 95% ethanol extract of VA leaves
- Vernonia amygdalina
- iNOS, inducible nitric oxide synthase
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Affiliation(s)
- Jia-Ying Wu
- Research and Development Centre for Natural Health Products, HKBU Institute for Research and Continuing Education, Shenzhen, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Jian-Hua Xie
- Department of Food and Biological Engineering, Zhangzhou Institute of Technology, China
| | - Ying-Jie Chen
- Research and Development Centre for Natural Health Products, HKBU Institute for Research and Continuing Education, Shenzhen, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xiu-Qiong Fu
- Research and Development Centre for Natural Health Products, HKBU Institute for Research and Continuing Education, Shenzhen, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Rui-Jun Wang
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yu-Yi Deng
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Shuo Wang
- Dalian Fusheng Natural Medicine Research Institute, China
| | - Hai-Xia Yu
- Jilin Yatai Traditional Chinese Medicine Innovation Research Institute, China
| | - Chun Liang
- Division of Life Science and State Key Lab of Molecular Neuroscience, Hong Kong University of Science and Technology, China
| | - Zhi-Ling Yu
- Research and Development Centre for Natural Health Products, HKBU Institute for Research and Continuing Education, Shenzhen, China; Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
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MacMullan MA, Wang P, Graham NA. Phospho-proteomics reveals that RSK signaling is required for proliferation of natural killer cells stimulated with IL-2 or IL-15. Cytokine 2022; 157:155958. [PMID: 35841827 DOI: 10.1016/j.cyto.2022.155958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/13/2022] [Accepted: 07/01/2022] [Indexed: 11/19/2022]
Abstract
Natural killer (NK) cells are cytotoxic lymphocytes that play a critical role in the innate immune system. Although cytokine signaling is crucial for the development, expansion, and cytotoxicity of NK cells, the signaling pathways stimulated by cytokines are not well understood. Here, we sought to compare the early signaling dynamics induced by the cytokines interleukin (IL)-2 and IL-15 using liquid chromatography-mass spectrometry (LC-MS)-based phospho-proteomics. Following stimulation of the immortalized NK cell line NK-92 with IL-2 or IL-15 for 5, 10, 15, or 30 min, we identified 8,692 phospho-peptides from 3,023 proteins. Comparing the kinetic profiles of 3,619 fully quantified phospho-peptides, we found that IL-2 and IL-15 induced highly similar signaling in NK-92 cells. Among the IL-2/IL-15-regulated phospho-peptides were both well-known signaling events like the JAK/STAT pathway and novel signaling events with potential functional significance including LCP1 pSer5, STMN1 pSer25, CHEK1 pSer286, STIM1 pSer608, and VDAC1 pSer104. Using bioinformatic approaches, we sought to identify kinases regulated by IL-2/IL-15 stimulation and found that the p90 ribosomal S6 kinase (p90RSK) family was activated by both cytokines. Using pharmacological inhibitors, we then discovered that RSK signaling is required for IL-2 and IL-15-induced proliferation in NK-92 cells. Taken together, our analysis represents the first phospho-proteomic characterization of cytokine signaling in NK cells and increases our understanding of how cytokine signaling regulates NK cell function.
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Affiliation(s)
- Melanie A MacMullan
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, United States.
| | - Pin Wang
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, United States; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, United States; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, United States.
| | - Nicholas A Graham
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, United States; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, United States; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, United States.
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Screening of potent STAT3-SH2 domain inhibitors from JAK/STAT compound library through molecular dynamics simulation. Mol Divers 2022:10.1007/s11030-022-10490-w. [PMID: 35831728 DOI: 10.1007/s11030-022-10490-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/24/2022] [Indexed: 10/17/2022]
Abstract
The Signal Transducer and Activator of Transcription 3 (STAT3) protein is activated consistently in the tumor cells and thus studied as a potent target for cancer prevention. The TYR705-phosphorylated (pTyr) STAT3 forms a homo-dimer by binding to its recognition site in the Src Homology 2 (SH2) domain of another STAT3 monomer, causing cellular survival, proliferation, inflammation, and tumor invasion. Many inhibitors of STAT3-SH2 have recently been identified using both computational and experimental approaches. In this study, we used molecular docking, Absorption, Distribution, Metabolism, and Excretion/Toxicological (ADME/tox) and molecular dynamics modeling to examine binding affinities and specificities of 191 inhibitor drugs from the SELLECKCHEM database. The binding free energies of the inhibitors were calculated by Induced Fit Docking (IFD) prime energy. The binding hotspots of STAT3-SH2 were evaluated via binding energy decomposition and hydrogen bond distribution analysis, and the inhibitor compound's stability was assessed through MD simulation. (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, Picroside I, Saikosaponin D, and Ginsenoside Rk1 were found to be the top hit inhibitor compounds. They exhibited an exceptional docking score, a low binding free energy, interacted with the key amino acid residue, and showed significant ADME/tox moderation. These compounds were further proved to be favorable by their stability in an MD simulation run for 100 ns using GROMACS software. The inhibitors (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, and Saikosaponin D show improved stability in molecular dynamic modeling and are expected to have a significant STAT3-SH2 inhibitory effect against cancer.
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36
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Witalisz-Siepracka A, Klein K, Zdársky B, Stoiber D. The Multifaceted Role of STAT3 in NK-Cell Tumor Surveillance. Front Immunol 2022; 13:947568. [PMID: 35865518 PMCID: PMC9294167 DOI: 10.3389/fimmu.2022.947568] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a member of the Janus kinase (JAK)-STAT pathway, which is one of the key pathways contributing to cancer. STAT3 regulates transcription downstream of many cytokines including interleukin (IL)-6 and IL-10. In cancer, STAT3 is mainly described as a tumor promoter driving tumor cell proliferation, resistance to apoptosis, angiogenesis and metastasis and aberrant activation of STAT3 is associated with poor prognosis. STAT3 is also an important driver of immune evasion. Among many other immunosuppressive mechanisms, STAT3 aids tumor cells to escape natural killer (NK) cell-mediated immune surveillance. NK cells are innate lymphocytes, which can directly kill malignant cells but also regulate adaptive immune responses and contribute to the composition of the tumor microenvironment. The inborn ability to lyse transformed cells renders NK cells an attractive tool for cancer immunotherapy. Here, we provide an overview of the role of STAT3 in the dynamic interplay between NK cells and tumor cells. On the one hand, we summarize the current knowledge on how tumor cell-intrinsic STAT3 drives the evasion from NK cells. On the other hand, we describe the multiple functions of STAT3 in regulating NK-cell cytotoxicity, cytokine production and their anti-tumor responses in vivo. In light of the ongoing research on STAT3 inhibitors, we also discuss how targeting STAT3 would affect the two arms of STAT3-dependent regulation of NK cell-mediated anti-tumor immunity. Understanding the complexity of this interplay in the tumor microenvironment is crucial for future implementation of NK cell-based immunotherapies.
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Affiliation(s)
- Agnieszka Witalisz-Siepracka
- Department of Pharmacology, Physiology and Microbiology, Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems, Austria
| | - Klara Klein
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Bernhard Zdársky
- Department of Pharmacology, Physiology and Microbiology, Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems, Austria
| | - Dagmar Stoiber
- Department of Pharmacology, Physiology and Microbiology, Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems, Austria
- *Correspondence: Dagmar Stoiber,
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Kenchappa RS, Dovas A, Argenziano MG, Meyer CT, Stopfer LE, Banu MA, Pereira B, Griffith J, Mohammad A, Talele S, Haddock A, Zarco N, Elmquist W, White F, Quaranta V, Sims P, Canoll P, Rosenfeld SS. Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma. Cell Rep 2022; 39:110991. [PMID: 35732128 PMCID: PMC10018805 DOI: 10.1016/j.celrep.2022.110991] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/27/2022] [Accepted: 06/01/2022] [Indexed: 01/19/2023] Open
Abstract
Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and epidermal growth factor receptor (EGFR), respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.
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Affiliation(s)
| | - Athanassios Dovas
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Michael G Argenziano
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Christian T Meyer
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
| | - Lauren E Stopfer
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Matei A Banu
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Brianna Pereira
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Jessica Griffith
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Afroz Mohammad
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Surabhi Talele
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ashley Haddock
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Natanael Zarco
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - William Elmquist
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Forest White
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Vito Quaranta
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
| | - Peter Sims
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Peter Canoll
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
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The minor allele of rs17427875 in long non-coding RNA-HOXA11-AS influences the prognosis of subarachnoid hemorrhage (SAH) via modulating miR-15a and STAT3 expression. Aging (Albany NY) 2022; 14:5075-5085. [PMID: 35700456 PMCID: PMC9271308 DOI: 10.18632/aging.204126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 02/18/2022] [Indexed: 11/25/2022]
Abstract
Background: HOAX11-AS was reported to promote the progression of liver cancer via the signaling pathway of miR-15a-3p/STAT3. In this study, we investigated the effect of rs17427875 on the prognosis of subarachnoid hemorrhage (SAH) and its underlying molecular mechanisms. Methods: 158 SAH patients were recruited and grouped according to their genotypes rs17427875. Peripheral blood and cerebrospinal fluid (CSF) samples were collected for subsequent analysis. Quantitative real-time PCR, luciferase assays, Western blot and ELISA were performed to analyze the correlations between the expression of lncRNA-HOXA11-AS, miR-15a, TNF-α and NF-κB. Results: The survival rate was remarkably higher in SAH patients carrying the AA genotype of rs17427875 when compared with those carrying the AT genotype. The expression of miR-15a was significantly repressed in the peripheral blood and CSF of SAH patients carrying the AT allele when compared with that in patients carrying the AA allele. MiR-15a showed a remarkable efficacy in inhibiting the luciferase activity of wild type lncRNA-HOXA11-AS and STAT3 in THP-1 cells. P-HOXA11-AS-T showed a stronger ability to suppress the expression of miR-15a and activate the expression of STAT3, TNF-α and NF-κB in THP-1 cells when compared with P-HOXA11-AS-A. Conclusions: The findings demonstrated that the presence of the minor allele of rs17427875 in lncRNA-HOXA11-AS could increase the expression level of lncRNA-HOXA11-AS, thus elevating the expression level of STAT3 via down-regulating miR-15a, and increased STAT3 expression could aggravate inflammation to cause poor prognosis of SAH. Therefore, the rs17427875 polymorphism can be used as a potential biomarker for the prognosis of SAH.
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Li S, Zhou H, Xie M, Zhang Z, Gou J, Yang J, Tian C, Ma K, Wang CY, Lu Y, Li Q, Peng W, Xiang M. Regenerating islet-derived protein 3 gamma (Reg3g) ameliorates tacrolimus-induced pancreatic β-cell dysfunction in mice by restoring mitochondrial function. Br J Pharmacol 2022; 179:3078-3095. [PMID: 35060126 DOI: 10.1111/bph.15803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 12/29/2021] [Accepted: 12/30/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Tacrolimus a first-line medication used after transplantation can induce β-cell dysfunction, causing new-onset diabetes mellitus (NODM). Regenerating islet-derived protein 3 gamma (Reg3g), a member of the pancreatic regenerative gene family, has been reported to improve type 1 diabetes by promoting β-cell regeneration. We aim to investigate the role of Reg3g in reversing tacrolimus-induced β-cell dysfunction and NODM in mice. EXPERIMENTAL APPROACH Circulating REG3A (the human homologue of mouse Reg3g) in heart transplantation patients treated with tacrolimus was detected. The glucose-stimulated insulin secretion and mitochondrial functions, including mitochondria membrane potential (MMP), mitochondria calcium, ATP production, oxygen consumption rate and mitochondrial morphology were investigated in β-cells. Additionally, effects of Reg3g on tacrolimus-induced NODM in mice were analysed. KEY RESULTS Circulating REG3A level in heart transplantation patients with NODM significantly decreased compared with those without diabetes. Tacrolimus down-regulated Reg3g via inhibiting STAT3-mediated transcription activation. Moreover, Reg3g restored glucose-stimulated insulin secretion suppressed by tacrolimus in β-cells by improving mitochondrial functions, including increased MMP, mitochondria calcium uptake, ATP production, oxygen consumption rate and contributing to an intact mitochondrial morphology. Mechanistically, Reg3g increased accumulation of pSTAT3(Ser727) in mitochondria by activating ERK1/2-STAT3 signalling pathway, leading to restoration of tacrolimus-induced mitochondrial impairment. Reg3g overexpression also effectively mitigated tacrolimus-induced NODM in mice. CONCLUSION AND IMPLICATIONS Reg3g can significantly ameliorate tacrolimus-induced β-cell dysfunction by restoring mitochondrial function in a pSTAT3(Ser727)-dependent manner. Our observations identify a novel Reg3g-mediated mechanism that is involved in tacrolimus-induced NODM and establish the novel role of Reg3g in reversing tacrolimus-induced β-cell dysfunction.
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Affiliation(s)
- Senlin Li
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Zhou
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengyuan Xie
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zijun Zhang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Gou
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Yang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Tian
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Ma
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong-Yi Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yi Lu
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Li
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wen Peng
- Department of General Practice, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ming Xiang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zhang Y, Jing Z, Cao X, Wei Q, He W, Zhang N, Liu Y, Yuan Q, Zhuang Z, Dong Y, Hong Z, Li J, Li P, Zhang L, Wang H, Li W. SOCS1, the feedback regulator of STAT1/3, inhibits the osteogenic differentiation of rat bone marrow mesenchymal stem cells. Gene 2022; 821:146190. [PMID: 35124149 DOI: 10.1016/j.gene.2022.146190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 11/25/2021] [Accepted: 12/06/2021] [Indexed: 11/30/2022]
Abstract
Our study showed that Signal transducer and activator of transcription (STAT)1 and STAT3 phosphorylation was firstly upregulated in the early stage of osteogenic differentiation (OD), and quickly eliminated in hours. Following with phosphorylation of STAT1/3, its downstream feedback regulator Suppressor of cytokine signaling 1 (SOCS1) protein also underwent a quick elevation. Further activation and deactivation of STAT1/3, by administrated with Colivelin and Nifuroxazide in Bone mesenchymal stem cells (BMSCs), increased and decreased SOCS1 expression, inhibited and promoted OD of BMSCs, respectively, as evidenced by Alizarin staining, alkaline phosphatase (ALP) activity, and determination of Run-related transcription factor 2 (RUNX2), Osteocalcin (OCN), ALP, and Bone sialoprotein (BSP). In addition, administration of Colivelin and Nifuroxazide caused and blocked inflammation and apoptosis of BMSCs. To further elucidate the role of STAT1/3-SOCS1 regulatory loop on OD of BMSCs, we overexpressed or silenced SOCS1 in BMSCs during OD. WB data showed that overexpression of SOCS1 repressed STAT1/3 phosphorylation, and knockdown of SOCS1 increased the phosphorylated STAT1/3. Further mechanism study showed that OD of BMSCs was elevated or reduced by SOCS1 overexpression or knockdown, respectively. The findings presenting indicated that the STAT1/3-SOCS1 axis may be exploited as an innovative strategy to enhance osteogenesis in regenerative medicine.
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Affiliation(s)
- Ying Zhang
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China; Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China.
| | - Zhenhao Jing
- Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China.
| | - Xiangyang Cao
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Qiushi Wei
- Institute of Orthopaedics of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China; The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China.
| | - Wei He
- Institute of Orthopaedics of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China; The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China.
| | - Ning Zhang
- Hunan University of Chinese Medicine, Zhengzhou, Henan 410208, China.
| | - Youwen Liu
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Qiang Yuan
- Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China.
| | - Zhikun Zhuang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China.
| | - Yipping Dong
- Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China.
| | - Zhinan Hong
- Institute of Orthopaedics of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China; The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China.
| | - Jitian Li
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Peifeng Li
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Leilei Zhang
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Haibin Wang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China.
| | - Wuyin Li
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
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Chen CL, Tseng PC, Satria RD, Nguyen TT, Tsai CC, Lin CF. Role of Glycogen Synthase Kinase-3 in Interferon-γ-Mediated Immune Hepatitis. Int J Mol Sci 2022; 23:ijms23094669. [PMID: 35563060 PMCID: PMC9101719 DOI: 10.3390/ijms23094669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/16/2022] [Accepted: 04/20/2022] [Indexed: 12/04/2022] Open
Abstract
Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a vital glycogen synthase regulator controlling glycogen synthesis, glucose metabolism, and insulin signaling. GSK-3 is widely expressed in different types of cells, and its abundant roles in cellular bioregulation have been speculated. Abnormal GSK-3 activation and inactivation may affect its original bioactivity. Moreover, active and inactive GSK-3 can regulate several cytosolic factors and modulate their diverse cellular functional roles. Studies in experimental liver disease models have illustrated the possible pathological role of GSK-3 in facilitating acute hepatic injury. Pharmacologically targeting GSK-3 is therefore suggested as a therapeutic strategy for liver protection. Furthermore, while the signaling transduction of GSK-3 facilitates proinflammatory interferon (IFN)-γ in vitro and in vivo, the blockade of GSK-3 can be protective, as shown by an IFN-γ-induced immune hepatitis model. In this study, we explored the possible regulation of GSK-3 and the potential relevance of GSK-3 blockade in IFN-γ-mediated immune hepatitis.
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Affiliation(s)
- Chia-Ling Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;
| | - Po-Chun Tseng
- Core Laboratory of Immune Monitoring, Office of Research & Development, Taipei Medical University, Taipei 110, Taiwan;
| | - Rahmat Dani Satria
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (R.D.S.); (T.T.N.)
- Department of Clinical Pathology and Laboratory Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
- Clinical Laboratory Installation, Dr. Sardjito Central General Hospital, Yogyakarta 55281, Indonesia
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Thi Thuy Nguyen
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (R.D.S.); (T.T.N.)
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Oncology, Hue University of Medicine and Pharmacy, Hue University, Hue City 530000, Vietnam
| | - Cheng-Chieh Tsai
- Department of Nursing, Chung Hwa University of Medical Technology, Tainan 703, Taiwan
- Department of Long Term Care Management, Chung Hwa University of Medical Technology, Tainan 703, Taiwan
- Correspondence: (C.-C.T.); (C.-F.L.)
| | - Chiou-Feng Lin
- Core Laboratory of Immune Monitoring, Office of Research & Development, Taipei Medical University, Taipei 110, Taiwan;
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (R.D.S.); (T.T.N.)
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (C.-C.T.); (C.-F.L.)
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Cheung KL, Jaganathan A, Hu Y, Xu F, Lejeune A, Sharma R, Caescu CI, Meslamani J, Vincek A, Zhang F, Lee K, Zaware N, Qayum AA, Ren C, Kaplan MH, He JC, Xiong H, Zhou MM. HIPK2 directs cell type-specific regulation of STAT3 transcriptional activity in Th17 cell differentiation. Proc Natl Acad Sci U S A 2022; 119:e2117112119. [PMID: 35344430 PMCID: PMC9168845 DOI: 10.1073/pnas.2117112119] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/11/2022] [Indexed: 12/25/2022] Open
Abstract
SignificanceSTAT3 (signal transducer and activator of transcription 3) is a master transcription factor that organizes cellular responses to cytokines and growth factors and is implicated in inflammatory disorders. STAT3 is a well-recognized therapeutic target for human cancer and inflammatory disorders, but how its function is regulated in a cell type-specific manner has been a major outstanding question. We discovered that Stat3 imposes self-directed regulation through controlling transcription of its own regulator homeodomain-interacting protein kinase 2 (Hipk2) in a T helper 17 (Th17) cell-specific manner. Our validation of the functional importance of the Stat3-Hipk2 axis in Th17 cell development in the pathogenesis of T cell-induced colitis in mice suggests an approach to therapeutically treat inflammatory bowel diseases that currently lack a safe and effective therapy.
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Affiliation(s)
- Ka Lung Cheung
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Anbalagan Jaganathan
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Yuan Hu
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Feihong Xu
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Alannah Lejeune
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Rajal Sharma
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Cristina I. Caescu
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Jamel Meslamani
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Adam Vincek
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Fan Zhang
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Kyung Lee
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Nilesh Zaware
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Amina Abdul Qayum
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Chunyan Ren
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Mark H. Kaplan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - John Cijiang He
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Huabao Xiong
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Ming-Ming Zhou
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Salem F, Li XZ, Hindi J, Casablanca NM, Zhong F, El Jamal SM, Haroon Al Rasheed MR, Li L, Lee K, Chan L, He JC. Activation of STAT3 signaling pathway in the kidney of COVID-19 patients. J Nephrol 2022; 35:735-743. [PMID: 34626364 PMCID: PMC8501346 DOI: 10.1007/s40620-021-01173-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 09/17/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Acute kidney injury is common in patients with COVID-19, however mechanisms of kidney injury remain unclear. Since cytokine storm is likely a cause of AKI and glomerular disease, we investigated the two major transcription factors, STAT3 and NF-kB, which are known to be activated by cytokines. METHODS This is an observational study of the postmortem kidneys of 50 patients who died with COVID-19 in the Mount Sinai Hospital during the first pandemic surge. All samples were reviewed under light microscopy, electron microscopy, and immunofluorescence by trained renal pathologists. In situ hybridization evaluation for SARS-CoV-2 and immunostaining of transcription factors STAT3 and NF-kB were performed. RESULTS Consistent with previous findings, acute tubular injury was the major pathological finding, together with global or focal glomerulosclerosis. We were not able to detect SARS-CoV-2 in kidney cells. ACE2 expression was reduced in the tubular cells of patients who died with COVID-19 and did not co-localize with TMPRSS2. SARS-CoV-2 was identified occasionally in the mononuclear cells in the peritubular capillary and interstitium. STAT3 phosphorylation at Tyr705 was increased in 2 cases in the glomeruli and in 3 cases in the tubulointerstitial compartments. Interestingly, STAT3 phosphorylation at Ser727 increased in 9 cases but only in the tubulointerstitial compartment. A significant increase in NF-kB phosphorylation at Ser276 was also found in the tubulointerstitium of the two patients with increased p-STAT3 (Tyr705). CONCLUSIONS Our findings suggest that, instead of tyrosine phosphorylation, serine phosphorylation of STAT3 is commonly activated in the kidney of patients with COVID-19.
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Affiliation(s)
- Fadi Salem
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Xue Zhu Li
- Department of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Judy Hindi
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nitzy Munoz Casablanca
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fang Zhong
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Siraj M El Jamal
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Li Li
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Kyung Lee
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Lili Chan
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Renal Program, James J Peters VAMC, Bronx, NY, USA.
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Clowers MJ, Moghaddam SJ. Cell Type-Specific Roles of STAT3 Signaling in the Pathogenesis and Progression of K-ras Mutant Lung Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14071785. [PMID: 35406557 PMCID: PMC8997152 DOI: 10.3390/cancers14071785] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Lung adenocarcinomas with mutations in the K-ras gene are hard to target pharmacologically and highly lethal. As a result, there is a need to identify other therapeutic targets that influence K-ras oncogenesis. One contender is STAT3, a transcription factor that is associated with K-ras mutations and aids tumor development and progression through tumor cell intrinsic and extrinsic mechanisms. In this review, we summarize the lung epithelial and infiltrating immune cells that express STAT3, the roles of STAT3 in K-ras mutant lung adenocarcinoma, and therapies that may be able to target STAT3. Abstract Worldwide, lung cancer, particularly K-ras mutant lung adenocarcinoma (KM-LUAD), is the leading cause of cancer mortality because of its high incidence and low cure rate. To treat and prevent KM-LUAD, there is an urgent unmet need for alternative strategies targeting downstream effectors of K-ras and/or its cooperating pathways. Tumor-promoting inflammation, an enabling hallmark of cancer, strongly participates in the development and progression of KM-LUAD. However, our knowledge of the dynamic inflammatory mechanisms, immunomodulatory pathways, and cell-specific molecular signals mediating K-ras-induced lung tumorigenesis is substantially deficient. Nevertheless, within this signaling complexity, an inflammatory pathway is emerging as a druggable target: signal transducer and activator of transcription 3 (STAT3). Here, we review the cell type-specific functions of STAT3 in the pathogenesis and progression of KM-LUAD that could serve as a new target for personalized preventive and therapeutic intervention for this intractable form of lung cancer.
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Affiliation(s)
- Michael J. Clowers
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Seyed Javad Moghaddam
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
- Correspondence:
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Zhang Y, Day K, Absher DM. STAT3-mediated allelic imbalance of novel genetic variant Rs1047643 and B-cell-specific super-enhancer in association with systemic lupus erythematosus. eLife 2022; 11:72837. [PMID: 35188103 PMCID: PMC8884724 DOI: 10.7554/elife.72837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 02/18/2022] [Indexed: 11/24/2022] Open
Abstract
Mapping of allelic imbalance (AI) at heterozygous loci has the potential to establish links between genetic risk for disease and biological function. Leveraging multi-omics data for AI analysis and functional annotation, we discovered a novel functional risk variant rs1047643 at 8p23 in association with systemic lupus erythematosus (SLE). This variant displays dynamic AI of chromatin accessibility and allelic expression on FDFT1 gene in B cells with SLE. We further found a B-cell restricted super-enhancer (SE) that physically contacts with this SNP-residing locus, an interaction that also appears specifically in B cells. Quantitative analysis of chromatin accessibility and DNA methylation profiles further demonstrated that the SE exhibits aberrant activity in B cell development with SLE. Functional studies identified that STAT3, a master factor associated with autoimmune diseases, directly regulates both the AI of risk variant and the activity of SE in cultured B cells. Our study reveals that STAT3-mediated SE activity and cis-regulatory effects of SNP rs1047643 at 8p23 locus are associated with B cell deregulation in SLE.
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Affiliation(s)
- Yanfeng Zhang
- HudsonAlpha Institute for Biotechnology, Huntsville, United States
| | | | - Devin M Absher
- HudsonAlpha Institute for Biotechnology, Huntsville, United States
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Salviolone from Salvia miltiorrhiza Roots Impairs Cell Cycle Progression, Colony Formation, and Metalloproteinase-2 Activity in A375 Melanoma Cells: Involvement of P21(Cip1/Waf1) Expression and STAT3 Phosphorylation. Int J Mol Sci 2022; 23:ijms23031121. [PMID: 35163058 PMCID: PMC8835475 DOI: 10.3390/ijms23031121] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 02/04/2023] Open
Abstract
Melanoma is a highly malignant solid tumor characterized by an elevated growth and propagation rate. Since, often, melanoma treatment cannot prevent recurrences and the appearance of metastasis, new anti-melanoma agents need to be discovered. Salvia miltiorrhiza roots are a source of diterpenoid derivatives, natural compounds with several biological activities, including antiproliferative and anticancer effects. Seven diterpenoid derivatives were purified from S. miltiorrhiza roots and identified by NMR and MS analysis. Tanshinone IIA and cryptotanshinone were detected as the main components of S. miltiorrhiza root ethanol extract. Although their antitumor activity is already known, they have been confirmed to induce a reduction in A375 and MeWo melanoma cell growth. Likewise, salviolone has been shown to impair the viability of melanoma cells without affecting the growth of normal melanocytes. The underlying anticancer activity of salviolone has been investigated and compared to that of cryptotanshinone in A375 cells, showing an increased P21 protein expression in a P53-dependent manner. In that way, salviolone, even more than cryptotanshinone, displays a multitarget effect on cell-cycle-related proteins. Besides, it modulates the phosphorylation level of the signal transducer and activator of transcription (STAT)3. Unexpectedly, salviolone and cryptotanshinone induce sustained activation of the extracellular signal-regulated kinases (ERK)1/2 and the protein kinase B (Akt). However, the blockage of ERK1/2 or Akt activities suggests that kinase activation does not hinder their ability to inhibit A375 cell growth. Finally, salviolone and cryptotanshinone inhibit to a comparable extent some crucial malignancy features of A375 melanoma cells, such as colony formation in soft agar and metalloproteinase-2 activity. In conclusion, it has been shown for the first time that salviolone, harboring a different molecular structure than tanshinone IIA and cryptotanshinone, exhibits a pleiotropic effect against melanoma by hampering cell cycle progression, STAT3 signaling, and malignant phenotype of A375 melanoma cells.
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de Mendonça ELSS, Fragoso MBT, de Oliveira JM, Xavier JA, Goulart MOF, de Oliveira ACM. Gestational Diabetes Mellitus: The Crosslink among Inflammation, Nitroxidative Stress, Intestinal Microbiota and Alternative Therapies. Antioxidants (Basel) 2022; 11:129. [PMID: 35052633 PMCID: PMC8773111 DOI: 10.3390/antiox11010129] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 12/30/2021] [Accepted: 01/04/2022] [Indexed: 01/09/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is characterized by a set of metabolic complications arising from adaptive failures to the pregnancy period. Estimates point to a prevalence of 3 to 15% of pregnancies. Its etiology includes intrinsic and extrinsic aspects of the progenitress, which may contribute to the pathophysiogenesis of GDM. Recently, researchers have identified that inflammation, oxidative stress, and the gut microbiota participate in the development of the disease, with potentially harmful effects on the health of the maternal-fetal binomial, in the short and long terms. In this context, alternative therapies were investigated from two perspectives: the modulation of the intestinal microbiota, with probiotics and prebiotics, and the use of natural products with antioxidant and anti-inflammatory properties, which may mitigate the endogenous processes of the GDM, favoring the health of the mother and her offspring, and in a future perspective, alleviating this critical public health problem.
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Affiliation(s)
- Elaine Luiza Santos Soares de Mendonça
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio 57072-970, Alagoas, Brazil; (E.L.S.S.d.M.); (M.B.T.F.); (J.M.d.O.); (J.A.X.)
| | - Marilene Brandão Tenório Fragoso
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio 57072-970, Alagoas, Brazil; (E.L.S.S.d.M.); (M.B.T.F.); (J.M.d.O.); (J.A.X.)
| | - Jerusa Maria de Oliveira
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio 57072-970, Alagoas, Brazil; (E.L.S.S.d.M.); (M.B.T.F.); (J.M.d.O.); (J.A.X.)
| | - Jadriane Almeida Xavier
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio 57072-970, Alagoas, Brazil; (E.L.S.S.d.M.); (M.B.T.F.); (J.M.d.O.); (J.A.X.)
| | - Marília Oliveira Fonseca Goulart
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio 57072-970, Alagoas, Brazil; (E.L.S.S.d.M.); (M.B.T.F.); (J.M.d.O.); (J.A.X.)
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Opposing Effects of Chelidonine on Tyrosine and Serine Phosphorylation of STAT3 in Human Uveal Melanoma Cells. Int J Mol Sci 2021; 22:ijms222312974. [PMID: 34884773 PMCID: PMC8658041 DOI: 10.3390/ijms222312974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 11/17/2022] Open
Abstract
STAT3 is a transcription factor that regulates various cellular processes with oncogenic potential, thereby promoting tumorigenesis when activated uncontrolled. STAT3 activation is mediated by its tyrosine phosphorylation, triggering dimerization and nuclear translocation. STAT3 also contains a serine phosphorylation site, with a postulated regulatory role in STAT3 activation and G2/M transition. Interleukin-6, a major activator of STAT3, is present in elevated concentrations in uveal melanomas, suggesting contribution of dysregulated STAT3 activation to their pathogenesis. Here, we studied the impact of chelidonine on STAT3 signaling in human uveal melanoma cells. Chelidonine, an alkaloid isolated from Chelidonium majus, disrupts microtubules, causes mitotic arrest and provokes cell death in numerous tumor cells. According to our flow cytometry and confocal microscopy data, chelidonine abrogated IL-6-induced activation and nuclear translocation, but amplified constitutive serine phosphorylation of STAT3. Both effects were restricted to a fraction of cells only, in an all-or-none fashion. A partial overlap could be observed between the affected subpopulations; however, no direct connection could be proven. This study is the first proof on a cell-by-cell basis for the opposing effects of a microtubule-targeting agent on the two types of STAT3 phosphorylation.
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Mishra S, Kumar S, Choudhuri KSR, Longkumer I, Koyyada P, Kharsyiemiong ET. Structural exploration with AlphaFold2-generated STAT3α structure reveals selective elements in STAT3α-GRIM-19 interactions involved in negative regulation. Sci Rep 2021; 11:23145. [PMID: 34848745 PMCID: PMC8633360 DOI: 10.1038/s41598-021-01436-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/28/2021] [Indexed: 11/18/2022] Open
Abstract
STAT3, an important transcription factor constitutively activated in cancers, is bound specifically by GRIM-19 and this interaction inhibits STAT3-dependent gene expression. GRIM-19 is therefore, considered as an inhibitor of STAT3 and may be an effective anti-cancer therapeutic target. While STAT3 exists in a dimeric form in the cytoplasm and nucleus, it is mostly present in a monomeric form in the mitochondria. Although GRIM-19-binding domains of STAT3 have been identified in independent experiments, yet the identified domains are not the same, and hence, discrepancies exist. Human STAT3-GRIM-19 complex has not been crystallised yet. Dictated by fundamental biophysical principles, the binding region, interactions and effects of hotspot mutations can provide us a clue to the negative regulatory mechanisms of GRIM-19. Prompted by the very nature of STAT3 being a challenging molecule, and to understand the structural basis of binding and interactions in STAT3α-GRIM-19 complex, we performed homology modelling and ab-initio modelling with evolutionary information using I-TASSER and avant-garde AlphaFold2, respectively, to generate monomeric, and subsequently, dimeric STAT3α structures. The dimeric form of STAT3α structure was observed to potentially exist in an anti-parallel orientation of monomers. We demonstrate that during the interactions with both unphosphorylated and phosphorylated STAT3α, the NTD of GRIM-19 binds most strongly to the NTD of STAT3α, in direct contrast to the earlier works. Key arginine residues at positions 57, 58 and 68 of GRIM-19 are mainly involved in the hydrogen-bonded interactions. An intriguing feature of these arginine residues is that these display a consistent interaction pattern across unphosphorylated and phosphorylated monomers as well as unphosphorylated dimers in STAT3α-GRIM-19 complexes. MD studies verified the stability of these complexes. Analysing the binding affinity and stability through free energy changes upon mutation, we found GRIM-19 mutations Y33P and Q61L and among GRIM-19 arginines, R68P and R57M, to be one of the top-most major and minor disruptors of binding, respectively. The proportionate increase in average change in binding affinity upon mutation was inclined more towards GRIM-19 mutants, leading to the surmise that GRIM-19 may play a greater role in the complex formation. These studies propound a novel structural perspective of STAT3α-GRIM-19 binding and inhibitory mechanisms in both the monomeric and dimeric forms of STAT3α as compared to that observed from the earlier experiments, these experimental observations being inconsistent among each other.
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Affiliation(s)
- Seema Mishra
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India.
| | - Santosh Kumar
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | | | - Imliyangla Longkumer
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Praveena Koyyada
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
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Gopalakrishnan S, Uma SK, Mohan G, Mohan A, Shanmugam G, Kumar VTV, J S, Chandrika SK, Vasudevan D, Nori SRC, Sathi SN, George S, Maliekal TT. SSTP1, a Host Defense Peptide, Exploits the Immunomodulatory IL6 Pathway to Induce Apoptosis in Cancer Cells. Front Immunol 2021; 12:740620. [PMID: 34867962 PMCID: PMC8639500 DOI: 10.3389/fimmu.2021.740620] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/27/2021] [Indexed: 12/30/2022] Open
Abstract
While the immunomodulatory pathways initiated in immune cells contribute to therapeutic response, their activation in cancer cells play a role in cancer progression. Also, many of the aberrantly expressed immunomodulators on cancer cells are considered as therapeutic targets. Here, we introduce host defense peptide (HDP), a known immuomodulator, as a therapeutic agent to target them. The cationic host defense peptides (HDPs), an integral part of the innate immune system, possess membranolytic activity, which imparts antimicrobial and antitumor efficacy to it. They act as immunomodulators by activating the immune cells. Though their antimicrobial function has been recently reassigned to immunoregulation, their antitumor activity is still attributed to its membranolytic activity. This membrane pore formation ability, which is proportional to the concentration of the peptide, also leads to side effects like hemolysis, limiting their therapeutic application. So, despite the identification of a variety of anticancer HDPs, their clinical utility is limited. Though HDPs are shown to exert the immunomodulatory activity through specific membrane targets on immune cells, their targets on cancer cells are unknown. We show that SSTP1, a novel HDP identified by shotgun cloning, binds to the active IL6/IL6Rα/gp130 complex on cancer cells, rearranging the active site residues. In contrast to the IL6 blockers inhibiting JAK/STAT activity, SSTP1 shifts the proliferative IL6/JAK/STAT signaling to the apoptotic IL6/JNK/AP1 pathway. In IL6Rα-overexpressing cancer cells, SSTP1 induces apoptosis at low concentration through JNK pathway, without causing significant membrane disruption. We highlight the importance of immunomodulatory pathways in cancer apoptosis, apart from its established role in immune cell regulation and cancer cell proliferation. Our study suggests that identification of the membrane targets for the promising anticancer HDPs might lead to the identification of new drugs for targeted therapy.
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Affiliation(s)
- Shyla Gopalakrishnan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Interdisciplinary Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Soumya Krishnan Uma
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Gayathri Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Amrutha Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Manipal Academy of Higher Education, Manipal, India
| | - Geetha Shanmugam
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Vineeth T. V. Kumar
- Interdisciplinary Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Sreekumar J
- Statistics, Section of Extension and Social Science, The Indian Council of Agricultural Research (ICAR) Central Tuber Crops Research Institute, Thiruvananthapuram, India
| | - Sivakumar K. Chandrika
- Genomics Core Facility, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | | | - Sai Ravi Chandra Nori
- Interdisciplinary Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Shijulal Nelson Sathi
- Interdisciplinary Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Sanil George
- Interdisciplinary Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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