|
1
|
Yang T, Chen J, He ZN, Li Z, Jiang M. Utilizing network pharmacology and experimental validation to explore the mechanisms of the Qijiafuzheng formula promoting CD8+ T-cell infiltration in the microenvironment of lung adenocarcinoma through STAT1/CXCL10. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2025:1-19. [PMID: 40029153 DOI: 10.1080/10286020.2025.2467311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 02/06/2025] [Accepted: 02/06/2025] [Indexed: 03/05/2025]
Abstract
Qijiafuzheng formula (QJFZF), a Traditional Chinese Medicine used to treat lung cancer and mitigate chemotherapy side effects, was studied to clarify its impact on the tumor immune microenvironment (TIME). Using network pharmacology and experimental validation, 39 overlapping targets were identified from 579 QJFZF-related and 752 lung adenocarcinoma (LUAD)-TIME targets. Key genes (CCL3, IL10, CXCL10, FOXP3, CD86) correlated negatively with tumor purity and positively with CD8+ T-cell infiltration. CXCL10 emerged as the core target, with experiments showing QJFZF activates the STAT1/CXCL10 pathway to enhance CD8+ T-cell recruitment in LUAD-TIME. This study elucidates QJFZF's immunomodulatory mechanisms, supporting its clinical application.
Collapse
Affiliation(s)
- Tao Yang
- TCM Department, Beijing Shijitan Hospital, Capital Medical University, Beijing100038, China
| | - Jian Chen
- Research Office, China Rehabilitation Research Center, Beijing100068, China
| | - Zhao-Nan He
- Research Office, China Rehabilitation Research Center, Beijing100068, China
| | - Zhong Li
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing100068, China
| | - Min Jiang
- TCM Department, Beijing Shijitan Hospital, Capital Medical University, Beijing100038, China
| |
Collapse
|
|
2
|
Karjalainen A, Witalisz-Siepracka A, Prchal-Murphy M, Martin D, Sternberg F, Krunic M, Dolezal M, Fortelny N, Farlik M, Macho-Maschler S, Lassnig C, Meissl K, Amenitsch L, Lederer T, Pohl E, Gotthardt D, Bock C, Decker T, Strobl B, Müller M. Cell-type-specific requirement for TYK2 in murine immune cells under steady state and challenged conditions. Cell Mol Life Sci 2025; 82:98. [PMID: 40025196 PMCID: PMC11872851 DOI: 10.1007/s00018-025-05625-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/31/2025] [Accepted: 02/17/2025] [Indexed: 03/04/2025]
Abstract
Tyrosine kinase 2 (TYK2) deficiency and loss or inhibition of kinase activity in men and mice leads to similar immune compromised phenotypes, predominantly through impairment of interferon (IFN) and interleukin 12 family responses. Here we relate the transcriptome changes to phenotypical changes observed in TYK2-deficient (Tyk2-/-) and TYK2 kinase-inactive (Tyk2K923E) mice in naïve splenic immune cells and upon ex vivo IFN treatment or in vivo tumor transplant infiltration. The TYK2 activities under homeostatic and both challenged conditions are highly cell-type-specific with respect to quantity and quality of transcriptionally dependent genes. The major impact of loss of TYK2 protein or kinase activity in splenic homeostatic macrophages, NK and CD8+ T cells and tumor-derived cytolytic cells is on IFN responses. While reportedly TYK2 deficiency leads to partial impairment of IFN-I responses, we identified cell-type-specific IFN-I-repressed gene sets completely dependent on TYK2 kinase activity. Reported kinase-inactive functions of TYK2 relate to signaling crosstalk, metabolic functions and cell differentiation or maturation. None of these phenotypes relates to respective enriched gene sets in the TYK2 kinase-inactive cell types. Nonetheless, the scaffolding functions of TYK2 are capable to change transcriptional activities at single gene levels and chromatin accessibility at promoter-distal regions upon cytokine treatment most prominently in CD8+ T cells. The cell-type-specific transcriptomic and epigenetic effects of TYK2 shed new light on the biology of this JAK family member and are relevant for current and future treatment of autoimmune and inflammatory diseases with TYK2 inhibitors.
Collapse
Affiliation(s)
- Anzhelika Karjalainen
- Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Agnieszka Witalisz-Siepracka
- Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
- Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems an Der Donau, Austria
| | - Michaela Prchal-Murphy
- Pharmacology and Toxicology, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - David Martin
- Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Felix Sternberg
- Physiology and Biophysics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
- Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, Vienna, Austria
| | - Milica Krunic
- Campus Tulln, University of Applied Sciences Wiener Neustadt, Wiener Neustadt, Austria
| | - Marlies Dolezal
- Platform Biostatistics and Bioinformatics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Nikolaus Fortelny
- Department of Biosciences and Medical Biology, Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria
| | - Matthias Farlik
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Sabine Macho-Maschler
- Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Caroline Lassnig
- Core Facility VetBiomodels, University of Veterinary Medicine, Vienna, Austria
| | - Katrin Meissl
- Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Lena Amenitsch
- Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Therese Lederer
- Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Elena Pohl
- Physiology and Biophysics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Dagmar Gotthardt
- Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems an Der Donau, Austria
| | - Christoph Bock
- Cemm Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Artificial Intelligence, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria
| | - Thomas Decker
- Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria
- Center for Molecular Biology, Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
| | - Birgit Strobl
- Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Mathias Müller
- Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
| |
Collapse
|
|
3
|
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.
Collapse
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.
| |
Collapse
|
|
4
|
Chhipa AS, Boscaro V, Gallicchio M, Patel S. The curious case of type I interferon signaling in cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189204. [PMID: 39477031 DOI: 10.1016/j.bbcan.2024.189204] [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: 06/23/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 11/05/2024]
Abstract
Cytokines are the crucial signaling proteins that mediate the crosstalks between the cells of tumor microenvironment (TME). Interferon-1 (IFN-1) are the important cytokines that are widely known for their tumor suppressive roles comprising of cancer cell intrinsic and extrinsic mechanisms. Despite having known antitumor effects, IFN-1 are also reported to have tumor promoting functions under varying circumstances. This dichotomy in the functions of IFN-1 is largely attributed to the acute and chronic activation of IFN-1 signaling in TME. The chronic activation of IFN-1 signaling in tumor cells results in altered stimulation of downstream pathways that result in the expression of tumor promoting proteins, while the acute IFN-1 signaling activation maintains its tumor inhibiting functions. In the present review, we have discussed the anti- and pro-tumor actions of IFN-1 signaling under acute and chronic IFN-1 signaling activation. We have also discussed the downstream changes in signaling components that result in tumor supportive functions of a constitutive IFN-1 signaling. We have further discussed the possible strategies to overcome the detrimental effects of chronic IFN-1 pathway activation and to successfully employ IFN-1 for their beneficial anti-tumor effects.
Collapse
Affiliation(s)
- Abu Sufiyan Chhipa
- Department of Pharmacology, Institute of Pharmacy, Nirma University, 382481 Ahmedabad, India; Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | - Valentina Boscaro
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | | | - Snehal Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, 382481 Ahmedabad, India.
| |
Collapse
|
|
5
|
Bieniussa L, Stolte C, Arampatzi P, Engert J, Völker J, Hagen R, Hackenberg S, Rak K. Inactivity of Stat3 in sensory and non-sensory cells of the mature cochlea. Front Mol Neurosci 2024; 17:1455136. [PMID: 39469187 PMCID: PMC11513353 DOI: 10.3389/fnmol.2024.1455136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/20/2024] [Indexed: 10/30/2024] Open
Abstract
Signal transducer and activator of transcription 3 (Stat3) plays a role in various cellular processes such as differentiation, inflammation, cell survival and microtubule dynamics, depending on the cell type and the activated signaling pathway. Stat3 is highly expressed in the hair cells and supporting cells of the cochlea and is essential for the differentiation of mouse hair cells in the early embryonic stage. However, it is unclear how Stat3 contributes to the correct function of cells in the organ of Corti postnatally. To investigate this, an inducible Cre/loxp system was used to knock out Stat3 in either the outer hair cells or the supporting cells. The results showed that the absence of Stat3 in either the outer hair cells or the supporting cells resulted in hearing loss without altering the morphology of the organ of Corti. Molecular analysis of the outer hair cells revealed an inflammatory process with increased cytokine production and upregulation of the NF-kB pathway. However, the absence of Stat3 in the supporting cells resulted in reduced microtubule stability. In conclusion, Stat3 is a critical protein for the sensory epithelium of the cochlea and hearing and functions in a cell and function-specific manner.
Collapse
Affiliation(s)
- L. Bieniussa
- Department of Oto-Rhino-Laryngology, University Hospital, Würzburg, Germany
| | - C. Stolte
- Department of Oto-Rhino-Laryngology, University Hospital, Würzburg, Germany
| | - P. Arampatzi
- Core Unit System Medicine, University of Würzburg, Würzburg, Germany
| | - J. Engert
- Department of Oto-Rhino-Laryngology, University Hospital, Würzburg, Germany
| | - J. Völker
- Department of Oto-Rhino-Laryngology, University Hospital, Würzburg, Germany
| | - R. Hagen
- Department of Oto-Rhino-Laryngology, University Hospital, Würzburg, Germany
| | - S. Hackenberg
- Department of Oto-Rhino-Laryngology, University Hospital, Würzburg, Germany
| | - K. Rak
- Department of Oto-Rhino-Laryngology, University Hospital, Würzburg, Germany
| |
Collapse
|
|
6
|
Wang Z, Liao X, He H, Guo X, Chen J. Targeting the STAT3 pathway with STAT3 degraders. Trends Pharmacol Sci 2024; 45:811-823. [PMID: 39117533 DOI: 10.1016/j.tips.2024.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/16/2024] [Accepted: 07/16/2024] [Indexed: 08/10/2024]
Abstract
Signal transducer and activator of transcription 3 (STAT3) has been widely considered as a therapeutic target for various diseases, especially tumors. Thus far, several STAT3 inhibitors have been advanced to clinical trials; however, the development of STAT3 inhibitors is hindered by numerous dilemmas. Fortunately, STAT3 degraders represent an alternative and promising strategy to block STAT3, attracting extensive research interest. Here, we analyze the recent advancements of STAT3 degraders, including proteolysis targeting chimeras (PROTACs) and small-molecule natural products, focusing on their structures, mechanisms, and biological activities. We discuss the potential opportunities and challenges for developing STAT3 degraders. It is hoped that this Review will provide insights into the discovery of potent STAT3-targeting drugs.
Collapse
Affiliation(s)
- Zhijie Wang
- Shenzhen Key Laboratory of Viral Oncology, Ministry of Science and Innovation, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China; Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xiaotong Liao
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Haiqi He
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xia Guo
- Shenzhen Key Laboratory of Viral Oncology, Ministry of Science and Innovation, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China.
| | - Jianjun Chen
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
| |
Collapse
|
|
7
|
Lin JX, Ge M, Liu CY, Holewinski R, Andresson T, Yu ZX, Gebregiorgis T, Spolski R, Li P, Leonard WJ. Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and T cell proliferation. Nat Commun 2024; 15:7372. [PMID: 39191751 PMCID: PMC11349758 DOI: 10.1038/s41467-024-50925-6] [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: 12/06/2023] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Cytokine-mediated STAT5 protein activation is vital for lymphocyte development and function. In vitro tyrosine phosphorylation of a C-terminal tyrosine is critical for activation of STAT5A and STAT5B; however, the importance of STAT5 tyrosine phosphorylation in vivo has not been assessed. Here we generate Stat5a and Stat5b tyrosine-to-phenylalanine mutant knockin mice and find they have greatly reduced CD8+ T-cell numbers and profoundly diminished IL-2-induced proliferation of these cells, and this correlates with reduced induction of Myc, pRB, a range of cyclins and CDKs, and a partial G1→S phase-transition block. These mutant CD8+ T cells also exhibit decreased IL-2-mediated activation of pERK and pAKT, which we attribute in part to diminished expression of IL-2Rβ and IL-2Rγ. Our findings thus demonstrate that tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling. Moreover, our transcriptomic and proteomic analyses elucidate the molecular basis of the IL-2-induced proliferation of CD8+ T cells.
Collapse
Affiliation(s)
- Jian-Xin Lin
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-1674, USA.
| | - Meili Ge
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-1674, USA
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, PR China
| | - Cheng-Yu Liu
- Transgenic Mouse Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-8018, USA
| | - Ronald Holewinski
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA
| | - Thorkell Andresson
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA
| | - Zu-Xi Yu
- Pathology Core, National Heart Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tesfay Gebregiorgis
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-1674, USA
| | - Rosanne Spolski
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-1674, USA
| | - Peng Li
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-1674, USA
- Amgen, Inc., 2301 Research Blvd., Rockville, MD, 20850, USA
| | - Warren J Leonard
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892-1674, USA.
| |
Collapse
|
|
8
|
Karim A, Garg R, Saikia B, Tiwari A, Sahu S, Malhotra M, Minz RW, Rawat A, Singh S, Suri D. Unraveling the unphosphorylated STAT3-unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome. Front Immunol 2024; 15:1332817. [PMID: 39229272 PMCID: PMC11369709 DOI: 10.3389/fimmu.2024.1332817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 04/09/2024] [Indexed: 09/05/2024] Open
Abstract
Background Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES. Objective This study aims to elucidate the role of unphosphorylated STAT3-unphosphorylated NF-κB (uSTAT3-uNF-κB) activation pathway in LOF STAT3 HIES patients. Methodology The mRNA expression of downstream molecules of unphosphorylated STAT3-unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter. Results A reduced expression of the downstream signaling molecules of the uSTAT3-uNF-κB complex pathway, viz., RANTES, STAT3, IL-6, IL-8, ICAM1, IL-8, ZFP36L2, CSF1, MRAS, and SOCS3, in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients. Conclusion The reduced expression of downstream signaling molecules, specially RANTES and STAT3, confirmed the impaired uSTAT3-uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.
Collapse
Affiliation(s)
- Adil Karim
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rashi Garg
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Biman Saikia
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Abha Tiwari
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Smrity Sahu
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Mehak Malhotra
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ranjana W. Minz
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amit Rawat
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Surjit Singh
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Deepti Suri
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| |
Collapse
|
|
9
|
Ritter J, Szelinski F, Aue A, Stefanski AL, Rincon-Arevalo H, Chen Y, Nitschke E, Dang VD, Wiedemann A, Schrezenmeier E, Lino AC, Dörner T. Elevated unphosphorylated STAT1 and IRF9 in T and B cells of primary sjögren's syndrome: Novel biomarkers for disease activity and subsets. J Autoimmun 2024; 147:103243. [PMID: 38788537 DOI: 10.1016/j.jaut.2024.103243] [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: 08/06/2023] [Revised: 03/23/2024] [Accepted: 05/05/2024] [Indexed: 05/26/2024]
Abstract
OBJECTIVES Autoreactive B cells and interferon (IFN) signature are hallmarks of primary sjögren's syndrome (pSS), but how IFN signaling pathways influence autoantibody production and clinical manifestations remain unclear. More detailed studies hold promise for improved diagnostic methodologies and personalized treatment. METHODS We analyzed peripheral blood T and B cell subsets from 34 pSS patients and 38 healthy donors (HDs) at baseline and upon stimulation regarding their expression levels of type I and II IFN signaling molecules (STAT1/2, IRF1, IRF9). Additionally, we investigated how the levels of these molecules correlated with serological and clinical characteristics and performed ROC analysis. RESULTS Patients showed elevated IFN pathway molecules, including STAT1, STAT2 and IRF9 among most T and B cell subsets. We found a reduced ratio of phosphorylated STAT1 and STAT2 in patients in comparison to HDs, although B cells from patients were highly responsive by increased phosphorylation upon IFN stimulation. Correlation matrices showed further interrelations between STAT1, IRF1 and IRF9 in pSS. Levels of STAT1 and IRF9 in T and B cells correlated with the IFN type I marker Siglec-1 (CD169) on monocytes. High levels of STAT1 and IRF9 within pSS B cells were significantly associated with hypergammaglobulinemia as well as anti-SSA/anti-SSB autoantibodies. Elevated STAT1 levels were found in patients with extraglandular disease and could serve as a biomarker for this subgroup (p < 0.01). Notably, IRF9 levels in T and B cells correlated with EULAR Sjögren's syndrome disease activity index (ESSDAI). CONCLUSION Here, we provide evidence that in active pSS patients, enhanced IFN signaling incl. unphosphorylated STAT1 and STAT2 with IRFs entertain chronic T and B cell activation. Furthermore, increased STAT1 levels candidate as biomarker of extraglandular disease, while IRF9 levels can serve as biomarker for disease activity.
Collapse
Affiliation(s)
- Jacob Ritter
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Academy, Charitéplatz 1, 10117, Berlin, Germany
| | - Franziska Szelinski
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany
| | - Arman Aue
- German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany; Department of Nephrology and Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Ana-Luisa Stefanski
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany
| | - Hector Rincon-Arevalo
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany; Department of Nephrology and Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Instituto de Investigaciones Médicas, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Yidan Chen
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany
| | - Eduard Nitschke
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany
| | - Van Duc Dang
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany
| | - Annika Wiedemann
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany
| | - Eva Schrezenmeier
- German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Academy, Charitéplatz 1, 10117, Berlin, Germany; Department of Nephrology and Intensive Care, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Andreia C Lino
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany
| | - Thomas Dörner
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany.
| |
Collapse
|
|
10
|
Devitt L, Westphal D, Pieger K, Schneider N, Bosserhoff AK, Kuphal S. NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma. Cell Commun Signal 2024; 22:256. [PMID: 38705997 PMCID: PMC11071257 DOI: 10.1186/s12964-024-01632-8] [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: 02/29/2024] [Accepted: 04/24/2024] [Indexed: 05/07/2024] Open
Abstract
BACKGROUND Melanoma is a highly heterogeneous cancer, in which frequent changes in activation of signaling pathways lead to a high adaptability to ever changing tumor microenvironments. The elucidation of cancer specific signaling pathways is of great importance, as demonstrated by the inhibitor of the common BrafV600E mutation PLX4032 in melanoma treatment. We therefore investigated signaling pathways that were influenced by neurotrophin NRN1, which has been shown to be upregulated in melanoma. METHODS Using a cell culture model system with an NRN1 overexpression, we investigated the influence of NRN1 on melanoma cells' functionality and signaling. We employed real time cell analysis and spheroid formation assays, while for investigation of molecular mechanisms we used a kinase phosphorylation kit as well as promotor activity analysis followed by mRNA and protein analysis. RESULTS We revealed that NRN1 interacts directly with the cleaved intracellular domain (NICD) of Notch1 and Notch3, causing a potential retention of NICD in the cytoplasm and thereby reducing the expression of its direct downstream target Hes1. This leads to decreased sequestration of JAK and STAT3 in a Hes1-driven phosphorylation complex. Consequently, our data shows less phosphorylation of STAT3 while presenting an accumulation of total protein levels of STAT3 in association with NRN1 overexpression. The potential of the STAT3 signaling pathway to act in both a tumor suppressive and oncogenic manner led us to investigate specific downstream targets - namely Vegf A, Mdr1, cMet - which were found to be upregulated under oncogenic levels of NRN1. CONCLUSIONS In summary, we were able to show that NRN1 links oncogenic signaling events between Notch and STAT3 in melanoma. We also suggest that in future research more attention should be payed to cellular regulation of signaling molecules outside of the classically known phosphorylation events.
Collapse
Affiliation(s)
- Lucia Devitt
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Dana Westphal
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT) Dresden, a partnership between German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Katharina Pieger
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Nadja Schneider
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Anja Katrin Bosserhoff
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Silke Kuphal
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany.
| |
Collapse
|
|
11
|
Janjua D, Thakur K, Aggarwal N, Chaudhary A, Yadav J, Chhokar A, Tripathi T, Joshi U, Senrung A, Bharti AC. Prognostic and therapeutic potential of STAT3: Opportunities and challenges in targeting HPV-mediated cervical carcinogenesis. Crit Rev Oncol Hematol 2024; 197:104346. [PMID: 38608913 DOI: 10.1016/j.critrevonc.2024.104346] [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: 02/09/2024] [Revised: 03/28/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024] Open
Abstract
Cervical cancer (CaCx) ranks as the fourth most prevalent cancer among women globally. Persistent infection of high-risk human papillomaviruses (HR-HPVs) is major etiological factor associated with CaCx. Signal Transducer and Activator of Transcription 3 (STAT3), a prominent member of the STAT family, has emerged as independent oncogenic driver. It is a target of many oncogenic viruses including HPV. How STAT3 influences HPV viral gene expression or gets affected by HPV is an area of active investigation. A better understanding of host-virus interaction will provide a prognostic and therapeutic window for CaCx control and management. In this comprehensive review, we delve into carcinogenic role of STAT3 in development of HPV-induced CaCx. With an emphasis on fascinating interplay between STAT3 and HPV genome, the review explores the diverse array of opportunities and challenges associated with this field to harness the prognostic and therapeutic potential of STAT3 in CaCx.
Collapse
Affiliation(s)
- Divya Janjua
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Apoorva Chaudhary
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India; Department of Zoology, Deshbandhu College, University of Delhi, Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Udit Joshi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Anna Senrung
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India; Department of Zoology, Daulat Ram College, University of Delhi, Delhi, India
| | - Alok Chandra Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India.
| |
Collapse
|
|
12
|
Casan JML, Seymour JF. Degraders upgraded: the rise of PROTACs in hematological malignancies. Blood 2024; 143:1218-1230. [PMID: 38170175 DOI: 10.1182/blood.2023022993] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/19/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024] Open
Abstract
ABSTRACT Targeted protein degradation (TPD) is a revolutionary approach to targeted therapy in hematological malignancies that potentially circumvents many constraints of existing small-molecule inhibitors. Heterobifunctional proteolysis-targeting chimeras (PROTACs) are the leading TPD drug class, with numerous agents now in clinical trials for a range of blood cancers. PROTACs harness the cell-intrinsic protein recycling infrastructure, the ubiquitin-proteasome system, to completely degrade target proteins. Distinct from targeted small-molecule inhibitor therapies, PROTACs can eliminate critical but conventionally "undruggable" targets, overcome resistance mechanisms to small-molecule therapies, and can improve tissue specificity and off-target toxicity. Orally bioavailable, PROTACs are not dependent on the occupancy-driven pharmacology inherent to inhibitory therapeutics, facilitating substoichiometric dosing that does not require an active or allosteric target binding site. Preliminary clinical data demonstrate promising therapeutic activity in heavily pretreated populations and novel technology platforms are poised to exploit a myriad of permutations of PROTAC molecular design to enhance efficacy and targeting specificity. As the field rapidly progresses and various non-PROTAC TPD drug candidates emerge, this review explores the scientific and preclinical foundations of PROTACs and presents them within common clinical contexts. Additionally, we examine the latest findings from ongoing active PROTAC clinical trials.
Collapse
Affiliation(s)
- Joshua M L Casan
- Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - John F Seymour
- Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| |
Collapse
|
|
13
|
Marié IJ, Lahiri T, Önder Ö, Elenitoba-Johnson KS, Levy DE. Structural determinants of mitochondrial STAT3 targeting and function. MITOCHONDRIAL COMMUNICATIONS 2024; 2:1-13. [PMID: 38500969 PMCID: PMC10947224 DOI: 10.1016/j.mitoco.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
Signal transducer and activator of transcription (STAT) 3 has been found within mitochondria in addition to its canonical role of shuttling between cytoplasm and nucleus during cytokine signaling. Mitochondrial STAT3 has been implicated in modulation of cellular metabolism, largely through effects on the respiratory electron transport chain. However, the structural requirements underlying mitochondrial targeting and function have remained unclear. Here, we show that mitochondrial STAT3 partitions between mitochondrial compartments defined by differential detergent solubility, suggesting that mitochondrial STAT3 is membrane associated. The majority of STAT3 was found in an SDS soluble fraction copurifying with respiratory chain proteins, including numerous components of the complex I NADH dehydrogenase, while a minor component was found with proteins of the mitochondrial translation machinery. Mitochondrial targeting of STAT3 required the amino-terminal domain, and an internal linker domain motif also directed mitochondrial translocation. However, neither the phosphorylation of serine 727 nor the presence of mitochondrial DNA was required for the mitochondrial localization of STAT3. Two cysteine residues in the STAT3 SH2 domain, which have been previously suggested to be targets for protein palmitoylation, were also not required for mitochondrial translocation, but were required for its function as an enhancer of complex I activity. These structural determinants of STAT3 mitochondrial targeting and function provide potential therapeutic targets for disrupting the activity of mitochondrial STAT3 in diseases such as cancer.
Collapse
Affiliation(s)
- Isabelle J. Marié
- Department of Pathology and Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, 10128, USA
| | - Tanaya Lahiri
- Department of Pathology and Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, 10128, USA
| | - Özlem Önder
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kojo S.J. Elenitoba-Johnson
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - David E. Levy
- Department of Pathology and Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, 10128, USA
| |
Collapse
|
|
14
|
Xu C, Wu P, Gao Q, Cai C, Fan K, Zhou J, Lei L, Chen L. Molecular characterization, expression analysis and subcellular location of the members of STAT family from spotted seabass (Lateolabrax maculatus). FISH & SHELLFISH IMMUNOLOGY 2024; 144:109241. [PMID: 37992914 DOI: 10.1016/j.fsi.2023.109241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/25/2023] [Accepted: 11/17/2023] [Indexed: 11/24/2023]
Abstract
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a pervasive intracellular signal transduction pathway, involving in biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. In this study, seven STAT genes, STAT1, STAT1-like, STAT2, STAT3, STAT4, STAT5a and STAT5b, were identified and characterized in spotted seabass (Lateolabrax maculatus). Analyses of multiple sequence alignment, genomic organization, phylogeny and conserved synteny were conducted to infer the evolutionary conservation of these genes in the STAT family. The results of the bioinformatics analysis assumed that STAT1 and STAT1-like might be homologous to STAT1a and STAT1b, respectively. Furthermore, the expression of the seven genes were detected in eight tissues of healthy spotted seabass, which revealed that they were expressed in a variety of tissues, mainly in gill, spleen and muscle, and extremely under-expression in liver. The expression of the seven genes in gill, head-kidney, spleen and intestine were significantly induced by lipopolysaccharide (LPS) or Edwardsiella tarda challenge. The expression of most of the LmSTATs were up-regulated, and the highest expression levels at 12 h after LPS stimulation, however, the LmSTATs were down-regulated by E. tarda infection. The results of subcellular localization show that the native LmSTAT1, LmSTAT1-like, LmSTAT2, LmSTAT3 and LmSTAT5a were localized in the cytoplasm, but they were translocated into the nucleus after LPS stimulation. Whereas, LmSTAT4 and LmSTAT5b were translocation into the nucleus whether with LPS stimulation or not. Overall, this is the first study to systematically revealed the localization of STAT members in fish, and indicated that LmSTATs participate in the process of protecting the host from pathogens invasion in the form of entry into nucleus.
Collapse
Affiliation(s)
- Chong Xu
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Ping Wu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qian Gao
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China.
| | - Chuanguo Cai
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Ke Fan
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Jie Zhou
- University of Chinese Academy of Sciences, Beijing, China
| | - Lina Lei
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Liangbiao Chen
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China
| |
Collapse
|
|
15
|
Liongue C, Sobah ML, Ward AC. Signal Transducer and Activator of Transcription Proteins at the Nexus of Immunodeficiency, Autoimmunity and Cancer. Biomedicines 2023; 12:45. [PMID: 38255152 PMCID: PMC10813391 DOI: 10.3390/biomedicines12010045] [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: 11/30/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/24/2024] Open
Abstract
The signal transducer and activator of transcription (STAT) family of proteins has been demonstrated to perform pivotal roles downstream of a myriad of cytokines, particularly those that control immune cell production and function. This is highlighted by both gain-of-function (GOF) and loss-of-function (LOF) mutations being implicated in various diseases impacting cells of the immune system. These mutations are typically inherited, although somatic GOF mutations are commonly observed in certain immune cell malignancies. This review details the growing appreciation of STAT proteins as a key node linking immunodeficiency, autoimmunity and cancer.
Collapse
Affiliation(s)
- Clifford Liongue
- School of Medicine, Deakin University, Waurn Ponds, Geelong, VIC 3216, Australia; (C.L.); (M.L.S.)
- Institute for Mental and Physical Health and Clinical Translation, Deakin University, Waurn Ponds, Geelong, VIC 3216, Australia
| | - Mohamed Luban Sobah
- School of Medicine, Deakin University, Waurn Ponds, Geelong, VIC 3216, Australia; (C.L.); (M.L.S.)
| | - Alister C. Ward
- School of Medicine, Deakin University, Waurn Ponds, Geelong, VIC 3216, Australia; (C.L.); (M.L.S.)
- Institute for Mental and Physical Health and Clinical Translation, Deakin University, Waurn Ponds, Geelong, VIC 3216, Australia
| |
Collapse
|
|
16
|
Leonard WJ, Lin JX. Strategies to therapeutically modulate cytokine action. Nat Rev Drug Discov 2023; 22:827-854. [PMID: 37542128 DOI: 10.1038/s41573-023-00746-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2023] [Indexed: 08/06/2023]
Abstract
Cytokines are secreted or membrane-presented molecules that mediate broad cellular functions, including development, differentiation, growth and survival. Accordingly, the regulation of cytokine activity is extraordinarily important both physiologically and pathologically. Cytokine and/or cytokine receptor engineering is being widely investigated to safely and effectively modulate cytokine activity for therapeutic benefit. IL-2 in particular has been extensively engineered, to create IL-2 variants that differentially exhibit activities on regulatory T cells to potentially treat autoimmune disease versus effector T cells to augment antitumour effects. Additionally, engineering approaches are being applied to many other cytokines such as IL-10, interferons and IL-1 family cytokines, given their immunosuppressive and/or antiviral and anticancer effects. In modulating the actions of cytokines, the strategies used have been broad, including altering affinities of cytokines for their receptors, prolonging cytokine half-lives in vivo and fine-tuning cytokine actions. The field is rapidly expanding, with extensive efforts to create improved therapeutics for a range of diseases.
Collapse
Affiliation(s)
- Warren J Leonard
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Jian-Xin Lin
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
17
|
Kumar A, Schwab M, Laborit Labrada B, Silveira MAD, Goudreault M, Fournier É, Bellmann K, Beauchemin N, Gingras AC, Bilodeau S, Laplante M, Marette A. SHP-1 phosphatase acts as a coactivator of PCK1 transcription to control gluconeogenesis. J Biol Chem 2023; 299:105164. [PMID: 37595871 PMCID: PMC10504565 DOI: 10.1016/j.jbc.2023.105164] [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: 12/02/2022] [Revised: 07/25/2023] [Accepted: 07/28/2023] [Indexed: 08/20/2023] Open
Abstract
We previously reported that the protein-tyrosine phosphatase SHP-1 (PTPN6) negatively regulates insulin signaling, but its impact on hepatic glucose metabolism and systemic glucose control remains poorly understood. Here, we use co-immunoprecipitation assays, chromatin immunoprecipitation sequencing, in silico methods, and gluconeogenesis assay, and found a new mechanism whereby SHP-1 acts as a coactivator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene to increase liver gluconeogenesis. SHP-1 is recruited to the regulatory regions of the PCK1 gene and interacts with RNA polymerase II. The recruitment of SHP-1 to chromatin is dependent on its association with the transcription factor signal transducer and activator of transcription 5 (STAT5). Loss of SHP-1 as well as STAT5 decrease RNA polymerase II recruitment to the PCK1 promoter and consequently PCK1 mRNA levels leading to blunted gluconeogenesis. This work highlights a novel nuclear role of SHP-1 as a key transcriptional regulator of hepatic gluconeogenesis adding a new mechanism to the repertoire of SHP-1 functions in metabolic control.
Collapse
Affiliation(s)
- Amit Kumar
- Faculté de Médecine, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Quebec, Canada
| | - Michael Schwab
- Faculté de Médecine, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Quebec, Canada
| | - Beisy Laborit Labrada
- Faculté de Médecine, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Quebec, Canada
| | - Maruhen Amir Datsch Silveira
- Centre de Recherche du CHU de Québec - Université Laval, Axe Oncologie, Québec, Quebec, Canada; Centre de Recherche sur le Cancer de l'Université Laval, Québec, Quebec, Canada; Département de biologie moléculaire, biochimie médicale et pathologie, Faculté de Médecine, Université Laval, Québec, Quebec, Canada
| | - Marilyn Goudreault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
| | - Éric Fournier
- Centre de Recherche du CHU de Québec - Université Laval, Axe Oncologie, Québec, Quebec, Canada; Centre de Recherche sur le Cancer de l'Université Laval, Québec, Quebec, Canada; Département de biologie moléculaire, biochimie médicale et pathologie, Faculté de Médecine, Université Laval, Québec, Quebec, Canada; Centre de recherche en données massives de l'Université Laval, Québec, Quebec, Canada
| | - Kerstin Bellmann
- Faculté de Médecine, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Quebec, Canada
| | - Nicole Beauchemin
- Department of Oncology, Medicine and Biochemistry, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Anne-Claude Gingras
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Steve Bilodeau
- Centre de Recherche du CHU de Québec - Université Laval, Axe Oncologie, Québec, Quebec, Canada; Centre de Recherche sur le Cancer de l'Université Laval, Québec, Quebec, Canada; Département de biologie moléculaire, biochimie médicale et pathologie, Faculté de Médecine, Université Laval, Québec, Quebec, Canada; Centre de recherche en données massives de l'Université Laval, Québec, Quebec, Canada
| | - Mathieu Laplante
- Faculté de Médecine, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Quebec, Canada; Centre de Recherche sur le Cancer de l'Université Laval, Québec, Quebec, Canada
| | - André Marette
- Faculté de Médecine, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Quebec, Canada; Institute of Nutrition and Functional Foods, Laval University, Québec, Quebec, Canada.
| |
Collapse
|
|
18
|
Zhao C, Wang H, Zhan W, Lv X, Ma X. Exploitation of Proximity-Mediated Effects in Drug Discovery: An Update of Recent Research Highlights in Perturbing Pathogenic Proteins and Correlated Issues. J Med Chem 2023; 66:10122-10149. [PMID: 37489834 DOI: 10.1021/acs.jmedchem.3c00079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
The utilization of proximity-mediated effects to perturb pathogenic proteins of interest (POIs) has emerged as a powerful strategic alternative to conventional drug design approaches based on target occupancy. Over the past three years, the burgeoning field of targeted protein degradation (TPD) has witnessed the expansion of degradable POIs to membrane-associated, extracellular, proteasome-resistant, and even microbial proteins. Beyond TPD, researchers have achieved the proximity-mediated targeted protein stabilization, the recruitment of intracellular immunophilins to disturb undruggable targets, and the nonphysiological post-translational modifications of POIs. All of these strides provide new avenues for innovative drug discovery aimed at battling human malignancies and other major diseases. This perspective presents recent research highlights and discusses correlated issues in developing therapeutic modalities that exploit proximity-mediated effects to modulate pathogenic proteins, thereby guiding future academic and industrial efforts in this field.
Collapse
Affiliation(s)
- Can Zhao
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Henian Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Wenhu Zhan
- iCarbonX (Shenzhen) Co., Ltd., Shenzhen, 518000, China
| | - Xiaoqing Lv
- College of Medicine, Jiaxing University, Jiaxing 314001, China
| | - Xiaodong Ma
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| |
Collapse
|
|
19
|
van den Brink A, Suárez Peredo Rodríguez MF, Foijer F. Chromosomal instability and inflammation: a catch-22 for cancer cells. Chromosome Res 2023; 31:19. [PMID: 37561163 PMCID: PMC10415485 DOI: 10.1007/s10577-023-09730-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/13/2023] [Accepted: 07/27/2023] [Indexed: 08/11/2023]
Abstract
Chromosomal instability (CIN), an increased rate of chromosomal segregation abnormalities, drives intratumor heterogeneity and affects most human cancers. In addition to chromosome copy number alterations, CIN results in chromosome(s) (fragments) being mislocalized into the cytoplasm in the form of micronuclei. Micronuclei can be detected by cGAS, a double-strand nucleic acid sensor, which will lead to the production of the second messenger 2'3'-cGAMP, activation of an inflammatory response, and downstream immune cell activation. However, the molecular network underlying the CIN-induced inflammatory response is still poorly understood. Furthermore, there is emerging evidence that cancers that display CIN circumvent this CIN-induced inflammatory response, and thus immune surveillance. The STAT1, STAT3, and NF-κB signaling cascades appear to play an important role in the CIN-induced inflammatory response. In this review, we discuss how these pathways are involved in signaling CIN in cells and how they are intertwined. A better understanding of how CIN is being signaled in cells and how cancer cells circumvent this is of the utmost importance for better and more selective cancer treatment.
Collapse
Affiliation(s)
- Anouk van den Brink
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands
| | - Maria F Suárez Peredo Rodríguez
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands.
| | - Floris Foijer
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands.
| |
Collapse
|
|
20
|
Grockowiak E, Korn C, Rak J, Lysenko V, Hallou A, Panvini FM, Williams M, Fielding C, Fang Z, Khatib-Massalha E, García-García A, Li J, Khorshed RA, González-Antón S, Baxter EJ, Kusumbe A, Wilkins BS, Green A, Simons BD, Harrison CN, Green AR, Lo Celso C, Theocharides APA, Méndez-Ferrer S. Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms. NATURE CANCER 2023; 4:1193-1209. [PMID: 37550517 PMCID: PMC10447237 DOI: 10.1038/s43018-023-00607-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 06/27/2023] [Indexed: 08/09/2023]
Abstract
Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.
Collapse
Affiliation(s)
- Elodie Grockowiak
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Claudia Korn
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Justyna Rak
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Veronika Lysenko
- Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland
| | - Adrien Hallou
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
- Wellcome Trust-CRUK Gurdon Institute, University of Cambridge, Cambridge, UK
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
- Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | - Francesca M Panvini
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Matthew Williams
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Claire Fielding
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Zijian Fang
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Eman Khatib-Massalha
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Andrés García-García
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Juan Li
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Reema A Khorshed
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, UK
- The Sir Francis Crick Institute, London, UK
| | - Sara González-Antón
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, UK
- The Sir Francis Crick Institute, London, UK
| | - E Joanna Baxter
- National Health Service Blood and Transplant, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
| | - Anjali Kusumbe
- The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | | | - Anna Green
- Guy's and Saint Thomas' NHS Foundation Trust, London, UK
| | - Benjamin D Simons
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
- Wellcome Trust-CRUK Gurdon Institute, University of Cambridge, Cambridge, UK
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
- Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | | | - Anthony R Green
- Department of Haematology, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK
| | - Cristina Lo Celso
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, UK
- The Sir Francis Crick Institute, London, UK
| | - Alexandre P A Theocharides
- Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland
| | - Simón Méndez-Ferrer
- National Health Service Blood and Transplant, Cambridge, UK.
- Department of Haematology, University of Cambridge, Cambridge, UK.
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
| |
Collapse
|
|
21
|
Landi E, Karabatas L, Rodríguez Gomez T, Salatino L, Scaglia P, Ramírez L, Keselman A, Braslavsky D, Sanguineti N, Pennisi P, Rey RA, Bergadá I, Jasper HG, Domené HM, Plazas PV, Domené S. An in vivo functional assay to characterize human STAT5B genetic variants during zebrafish development. Hum Mol Genet 2023; 32:2473-2484. [PMID: 37162340 DOI: 10.1093/hmg/ddad078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/19/2023] [Accepted: 05/07/2023] [Indexed: 05/11/2023] Open
Abstract
Growth hormone (GH) binding to GH receptor activates janus kinase 2 (JAK2)-signal transducer and activator of transcription 5b (STAT5b) pathway, which stimulates transcription of insulin-like growth factor-1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3) and insulin-like growth factor acid-labile subunit (IGFALS). Although STAT5B deficiency was established as an autosomal recessive disorder, heterozygous dominant-negative STAT5B variants have been reported in patients with less severe growth deficit and milder immune dysfunction. We developed an in vivo functional assay in zebrafish to characterize the pathogenicity of three human STAT5B variants (p.Ala630Pro, p.Gln474Arg and p.Lys632Asn). Overexpression of human wild-type (WT) STAT5B mRNA and its variants led to a significant reduction of body length together with developmental malformations in zebrafish embryos. Overexpression of p.Ala630Pro, p.Gln474Arg or p.Lys632Asn led to an increased number of embryos with pericardial edema, cyclopia and bent spine compared with WT STAT5B. Although co-injection of WT and p.Gln474Arg and WT and p.Lys632Asn STAT5B mRNA in zebrafish embryos partially or fully rescues the length and the developmental malformations in zebrafish embryos, co-injection of WT and p.Ala630Pro STAT5B mRNA leads to a greater number of embryos with developmental malformations and a reduction in body length of these embryos. These results suggest that these variants could interfere with endogenous stat5.1 signaling through different mechanisms. In situ hybridization of zebrafish embryos overexpressing p.Gln474Arg and p.Lys632Asn STAT5B mRNA shows a reduction in igf1 expression. In conclusion, our study reveals the pathogenicity of the STAT5B variants studied.
Collapse
Affiliation(s)
- Estefanía Landi
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Liliana Karabatas
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Tomás Rodríguez Gomez
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Lucía Salatino
- Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires (UBA), Paraguay 2155, C1121ABG, Buenos Aires, Argentina
| | - Paula Scaglia
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Laura Ramírez
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Ana Keselman
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Débora Braslavsky
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Nora Sanguineti
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Patricia Pennisi
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Rodolfo A Rey
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Ignacio Bergadá
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Héctor G Jasper
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Horacio M Domené
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| | - Paola V Plazas
- Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires (UBA), Paraguay 2155, C1121ABG, Buenos Aires, Argentina
| | - Sabina Domené
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez Buenos Aires C1425EFD, Argentina
| |
Collapse
|
|
22
|
Ott N, Faletti L, Heeg M, Andreani V, Grimbacher B. JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences. J Clin Immunol 2023:10.1007/s10875-023-01483-x. [PMID: 37140667 DOI: 10.1007/s10875-023-01483-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 04/01/2023] [Indexed: 05/05/2023]
Abstract
The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway's architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases.
Collapse
Affiliation(s)
- Nils Ott
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Laura Faletti
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Maximilian Heeg
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Division of Biological Sciences, Department of Molecular Biology, University of California, La Jolla, San Diego, CA, USA
| | - Virginia Andreani
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bodo Grimbacher
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- DZIF - German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany
- CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
| |
Collapse
|
|
23
|
Al-Hetty HRAK, Abdulameer SJ, Alkubaisy SA, Zaid SA, Jalil AT, Jasim IK. STAT3 signaling in pancreatic ductal adenocarcinoma: a candidate therapeutic target. Pathol Res Pract 2023; 245:154425. [PMID: 37019018 DOI: 10.1016/j.prp.2023.154425] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 03/19/2023] [Accepted: 03/21/2023] [Indexed: 04/05/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis which is lethal in over 90% of cases despite the standard therapies. Mainly activated by Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) is a key transcription factor, capable of exerting the expression of multitude of genes involved in survival. Moreover, STAT3 activity is regulated by the interleukin 28 receptor α (IL28RA) and glutathione s-transferase mu-3 (GSTM3), up-regulation of both contributes to the invasiveness of pancreatic cancer cells. In this regard, STAT3 overactivity has an important pathogenic role in the development of PDAC as it is associated with enhanced cell proliferation, survival, angiogenesis, and metastasis. STAT3-associated expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 3 and 9 are implicated in the angiogenic and metastatic behavior of the PDAC. Multitude of evidence underline the protective role of STAT3 inhibition against PDAC both in cell cultures and in tumor grafts. However, specific inhibition of STAT3 was not feasible until recently, when a selective potent chemical STAT3 inhibitor, termed N4, were developed and it turned out to be highly effective against PDAC in vitro, as well as in vivo. This review aims to discuss the most recent advances in our understanding of STAT3 role in the pathogenesis of PDAC and its therapeutic applications.
Collapse
|
|
24
|
Kelm JM, Pandey DS, Malin E, Kansou H, Arora S, Kumar R, Gavande NS. PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy. Mol Cancer 2023; 22:62. [PMID: 36991452 PMCID: PMC10061819 DOI: 10.1186/s12943-022-01707-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 12/23/2022] [Indexed: 03/31/2023] Open
Abstract
Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design.
Collapse
Affiliation(s)
- Jeremy M Kelm
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA
| | - Deepti S Pandey
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA
| | - Evan Malin
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA
| | - Hussein Kansou
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA
| | - Sahil Arora
- Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Raj Kumar
- Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Navnath S Gavande
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA.
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
| |
Collapse
|
|
25
|
Hathaway CA, Rice MS, Collins LC, Chen D, Frank DA, Walker S, Clevenger CV, Tamimi RM, Tworoger SS, Hankinson SE. Prolactin levels and breast cancer risk by tumor expression of prolactin-related markers. Breast Cancer Res 2023; 25:24. [PMID: 36882838 PMCID: PMC9990334 DOI: 10.1186/s13058-023-01618-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 02/11/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND Higher circulating prolactin has been associated with increased breast cancer risk. Prolactin binding to the prolactin receptor (PRLR) can activate the transcription factor STAT5, thus, we examined the association between plasma prolactin and breast cancer risk by tumor expression of PRLR, STAT5, and the upstream kinase JAK2. METHODS Using data from 745 cases and 2454 matched controls in the Nurses' Health Study, we conducted polytomous logistic regression to examine the association between prolactin (> 11 ng/mL vs. ≤ 11 ng/mL) measured within 10 years of diagnosis and breast cancer risk by PRLR (nuclear [N], cytoplasmic [C]), phosphorylated STAT5 (pSTAT5; N, C), and phosphorylated JAK2 (pJAK2; C) tumor expression. Analyses were conducted separately in premenopausal (n = 168 cases, 765 controls) and postmenopausal women (n = 577 cases, 1689 controls). RESULTS In premenopausal women, prolactin levels > 11 ng/mL were positively associated with risk of tumors positive for pSTAT5-N (OR 2.30, 95% CI 1.02-5.22) and pSTAT5-C (OR 1.64, 95% CI 1.01-2.65), but not tumors that were negative for these markers (OR 0.98, 95% CI 0.65-1.46 and OR 0.73, 95% CI 0.43-1.25; p-heterogeneity = 0.06 and 0.02, respectively). This was stronger when tumors were positive for both pSTAT5-N and pSTAT5-C (OR 2.88, 95% CI 1.14-7.25). No association was observed for PRLR or pJAK2 (positive or negative) and breast cancer risk among premenopausal women. Among postmenopausal women, plasma prolactin levels were positively associated with breast cancer risk irrespective of PRLR, pSTAT5, or pJAK2 expression (all p-heterogeneity ≥ 0.21). CONCLUSION We did not observe clear differences in the association between plasma prolactin and breast cancer risk by tumor expression of PRLR or pJAK2, although associations for premenopausal women were observed for pSTAT5 positive tumors only. While additional studies are needed, this suggests that prolactin may act on human breast tumor development through alternative pathways.
Collapse
Affiliation(s)
- Cassandra A Hathaway
- Department of Cancer Epidemiology, Moffitt Cancer Center, 13131 Magnolia Drive, Tampa, FL, 33612, USA.
| | - Megan S Rice
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Laura C Collins
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Dilys Chen
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
- Royal Columbian Hospital, University of British Columbia, Vancouver, Canada
| | - David A Frank
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Sarah Walker
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Charles V Clevenger
- Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA
| | - Rulla M Tamimi
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Shelley S Tworoger
- Department of Cancer Epidemiology, Moffitt Cancer Center, 13131 Magnolia Drive, Tampa, FL, 33612, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Susan E Hankinson
- Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA
| |
Collapse
|
|
26
|
Zhang C, Wang J, Song X, Yu D, Guo B, Pang Y, Yin X, Zhao S, Deng H, Zhang S, Deng W. STAT3 potentiates RNA polymerase I-directed transcription and tumor growth by activating RPA34 expression. Br J Cancer 2023; 128:766-782. [PMID: 36526675 PMCID: PMC9977892 DOI: 10.1038/s41416-022-02098-6] [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: 05/24/2022] [Revised: 11/25/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Deregulation of either RNA polymerase I (Pol I)-directed transcription or expression of signal transducer and activator of transcription 3 (STAT3) correlates closely with tumorigenesis. However, the connection between STAT3 and Pol I-directed transcription hasn't been investigated. METHODS The role of STAT3 in Pol I-directed transcription was determined using combined techniques. The regulation of tumor cell growth mediated by STAT3 and Pol I products was analyzed in vitro and in vivo. RNAseq, ChIP assays and rescue assays were used to uncover the mechanism of Pol I transcription mediated by STAT3. RESULTS STAT3 expression positively correlates with Pol I product levels and cancer cell growth. The inhibition of STAT3 or Pol I products suppresses cell growth. Mechanistically, STAT3 activates Pol I-directed transcription by enhancing the recruitment of the Pol I transcription machinery to the rDNA promoter. STAT3 directly activates Rpa34 gene transcription by binding to the RPA34 promoter, which enhances the occupancies of the Pol II transcription machinery factors at this promoter. Cancer patients with RPA34 high expression lead to poor survival probability and short survival time. CONCLUSION STAT3 potentiates Pol I-dependent transcription and tumor cell growth by activating RPA34 in vitro and in vivo.
Collapse
Affiliation(s)
- Cheng Zhang
- School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Juan Wang
- School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
- School of Materials and Metallurgy, Wuhan University of Science and Technology, Wuhan, 430081, China
| | - Xiaoye Song
- School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Deen Yu
- School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Baoqiang Guo
- Department of Life Sciences, Manchester Metropolitan University, Manchester, M15 6BH, UK
| | - Yaoyu Pang
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3GE, UK
| | - Xiaomei Yin
- School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Shasha Zhao
- School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China.
| | - Huan Deng
- School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China.
| | - Shihua Zhang
- School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China.
| | - Wensheng Deng
- School of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China.
| |
Collapse
|
|
27
|
Tang FL, Zhang XG, Ke PY, Liu J, Zhang ZJ, Hu DM, Gu J, Zhang H, Guo HK, Zang QW, Huang R, Ma YL, Kwan P. MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription. Neurobiol Dis 2023; 181:106103. [PMID: 36997128 DOI: 10.1016/j.nbd.2023.106103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 02/21/2023] [Accepted: 03/23/2023] [Indexed: 03/31/2023] Open
Abstract
Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain protein 5 gene (MBD5) are known to cause epilepsy. However, the function and mechanism of MBD5 in epilepsy remain elusive. Here, we found that MBD5 was mainly localized in the pyramidal cells and granular cells of mouse hippocampus, and its expression was increased in the brain tissues of mouse models of epilepsy. Exogenous overexpression of MBD5 inhibited the transcription of the signal transducer and activator of transcription 1 gene (Stat1), resulting in increased expression of N-methyl-d-aspartate receptor (NMDAR) subunit 1 (GluN1), 2A (GluN2A) and 2B (GluN2B), leading to aggravation of the epileptic behaviour phenotype in mice. The epileptic behavioural phenotype was alleviated by overexpression of STAT1 which reduced the expression of NMDARs, and by the NMDAR antagonist memantine. These results indicate that MBD5 accumulation affects seizures through STAT1-mediated inhibition of NMDAR expression in mice. Collectively, our findings suggest that the MBD5-STAT1-NMDAR pathway may be a new pathway that regulates the epileptic behavioural phenotype and may represent a new treatment target.
Collapse
|
|
28
|
Ugolini F, Szumera-Ciećkiewicz A, Baroni G, Nesi G, Mandalà M, Ferrone S, Massi D. Differential HLA class I subunit (A, B, C heavy chain and β 2-microglobulin) expression levels in normal tissues. Virchows Arch 2023; 482:359-368. [PMID: 36437414 PMCID: PMC9931818 DOI: 10.1007/s00428-022-03459-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 11/29/2022]
Abstract
Human leukocyte antigen (HLA) class I subunit expression level in primary and metastatic lesions has been characterized in many cancer types utilizing formalin-fixed and paraffin-embedded (FFPE) tissue sections as substrates in immunohistochemical reactions. The evaluation of the results of these studies has been hampered by the scant information about HLA class I subunit expression level in normal tissues. To address this unmet need, we have analyzed the HLA class I subunit expression level in FFPE sections of normal tissues.Two tissue microarray (TMA) blocks were constructed from archived FFPE tissue samples of a wide number of human normal tissues. The expression level of HLA-A, HLA-B, HLA-C heavy chains and β2-microglobulin (β2-M) was evaluated by IHC staining, with mAb HC-A2, mAb HC-10, and mAb NAMB1, respectively. The staining was scored according to its intensity.According to their staining patterns with the three mAbs tested, normal tissues can be divided into four groups: (i) tissues displaying moderate/strong staining patterns, (ii) tissues displaying barely detectable staining patterns, (iii) tissues displaying differential staining patterns, and (iv) tissues with no detectable staining. The ubiquitous expression pattern for HLA-A, B, C heavy chain and β2-M was found only at the endothelial level; the stroma was negative except for fibroblasts in all the tissues analyzed. Our data suggest that, contrary to the general postulate, HLA class I subunit expression is not detectable in all nucleated cells. This information provides a useful background to evaluate changes in HLA class I subunit expression associated with the malignant transformation of cells.
Collapse
Affiliation(s)
- Filippo Ugolini
- Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Anna Szumera-Ciećkiewicz
- Department of Pathology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
- Diagnostic Hematology Department, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Gianna Baroni
- Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Gabriella Nesi
- Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Mario Mandalà
- Unit of Medical Oncology, University of Perugia, Perugia, Italy
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Daniela Massi
- Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
| |
Collapse
|
|
29
|
Sun H, Ma D, Cheng Y, Li J, Zhang W, Jiang T, Li Z, Li X, Meng H. The JAK-STAT Signaling Pathway in Epilepsy. Curr Neuropharmacol 2023; 21:2049-2069. [PMID: 36518035 PMCID: PMC10556373 DOI: 10.2174/1570159x21666221214170234] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 11/08/2022] [Accepted: 11/21/2022] [Indexed: 12/16/2022] Open
Abstract
Epilepsy is defined as spontaneous recurrent seizures in the brain. There is increasing evidence that inflammatory mediators and immune cells are involved in epileptic seizures. As more research is done on inflammatory factors and immune cells in epilepsy, new targets for the treatment of epilepsy will be revealed. The Janus kinase-signal transducer and transcriptional activator (JAKSTAT) signaling pathway is strongly associated with many immune and inflammatory diseases, At present, more and more studies have found that the JAK-STAT pathway is involved in the development and development of epilepsy, indicating the JAK-STAT pathway's potential promise as a target in epilepsy treatment. In this review, we discuss the composition, activation, and regulation of the JAK-STAT pathway and the relationship between the JAK-STAT pathway and epilepsy. In addition, we summarize the common clinical inhibitors of JAK and STAT that we would expect to be used in epilepsy treatment in the future.
Collapse
Affiliation(s)
- Huaiyu Sun
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Di Ma
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Yu Cheng
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Jiaai Li
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Wuqiong Zhang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Ting Jiang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Zhaoran Li
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Xuewei Li
- Department of Radiology, The First Hospital of Jilin University, Changchun, China
| | - Hongmei Meng
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
30
|
Zhu B, Zheng J, Hong G, Bai T, Qian W, Liu J, Hou X. L-Fucose inhibits the progression of cholangiocarcinoma by causing microRNA-200b overexpression. Chin Med J (Engl) 2022; 135:2956-2967. [PMID: 36728287 PMCID: PMC10106127 DOI: 10.1097/cm9.0000000000002368] [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: 03/01/2022] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a malignant biliary tract tumor with an extremely poor prognosis. There is an urgent demand to explore novel therapeutic strategies. L-fucose has been confirmed to participate in anti-inflammation and antitumor activities. However, the effect of L-fucose on the progression of CCA has not been well investigated. This study aimed to determine whether L-fucose induced the inhibition of CCA and its possible mechanism. METHODS The anti-growth activity was determined using Cell Counting Kit-8 assay, colony formation assays, Annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) assay, and cell cycle analysis. The anti-metastasis activity was determined by wound healing, transwell, and invasion assays. The anti-angiogenesis activity was determined by tube formation and transwell assays. MicroRNAs that may be involved in the L-fucose-induced CCA inhibition was analyzed using bioinformatics methods. The preclinical therapeutic efficacy was mainly estimated by ultrasound in xenograft nude mouse models. Differences were analyzed via Student's t test or one-way analysis of variance. RESULTS L-Fucose induced apoptosis and G0/G1 cell cycle arrest, inhibited cell epithelial-mesenchymal transition of CCA cells, and additionally inhibited tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, leading to a decrease in cell proliferation, metastasis, and angiogenesis. Mechanistically, L-fucose induced microRNA-200b (miR-200b) upregulation, and mitogen-activated protein kinase 7 (MAPK7) downregulation was found to be targeted by miR-200b, with decreased cell proliferation and metastasis. Additionally, phosphorylated signal transducer and activator of transcription 3 was found to be downregulated after L-fucose treatment. Finally, in vivo experiments in CCA xenograft models also confirmed the antitumor properties of L-fucose. CONCLUSION L-Fucose inhibited the progression of CCA via the miR-200b/MAPK7 and signal transducer and activator of transcription 3 signaling pathways.
Collapse
Affiliation(s)
- Biqiang Zhu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Jingjing Zheng
- Department of Diagnostic Medical Sonography, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China
| | - Gaichao Hong
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Tao Bai
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Wei Qian
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Jinsong Liu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| |
Collapse
|
|
31
|
Liu Z, Hu M, Yang Y, Du C, Zhou H, Liu C, Chen Y, Fan L, Ma H, Gong Y, Xie Y. An overview of PROTACs: a promising drug discovery paradigm. MOLECULAR BIOMEDICINE 2022; 3:46. [PMID: 36536188 PMCID: PMC9763089 DOI: 10.1186/s43556-022-00112-0] [Citation(s) in RCA: 122] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022] Open
Abstract
Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin-proteasome system. Currently, about 20-25% of all protein targets are being studied, and most works focus on their enzymatic functions. Unlike small molecules, PROTACs inhibit the whole biological function of the target protein by binding to the target protein and inducing subsequent proteasomal degradation. PROTACs compensate for limitations that transcription factors, nuclear proteins, and other scaffolding proteins are difficult to handle with traditional small-molecule inhibitors. Currently, PROTACs have successfully degraded diverse proteins, such as BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 and ARV-471 exhibited excellent efficacy in clinical II trials. However, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood. And how to rationally design an efficient PROTACs and optimize it to be orally effective poses big challenges for researchers. In this review, we summarize the features of PROTAC technology, analyze the detail of general principles for designing efficient PROTACs, and discuss the typical application of PROTACs targeting different protein categories. In addition, we also introduce the progress of relevant clinical trial results of representative PROTACs and assess the challenges and limitations that PROTACs may face. Collectively, our studies provide references for further application of PROTACs.
Collapse
Affiliation(s)
- Zi Liu
- grid.13291.380000 0001 0807 1581State Key Laboratory of Biotherapy and Cancer Center, Department of Laboratory Medicine, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 China
| | - Mingxing Hu
- grid.13291.380000 0001 0807 1581State Key Laboratory of Biotherapy and Cancer Center, Department of Laboratory Medicine, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 China
| | - Yu Yang
- grid.13291.380000 0001 0807 1581State Key Laboratory of Biotherapy and Cancer Center, Department of Laboratory Medicine, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 China
| | - Chenghao Du
- grid.42505.360000 0001 2156 6853Department of Biological Sciences, USC Dana and David Dornsife College of Letters, Arts and Sciences, Los Angeles, 90089 USA
| | - Haoxuan Zhou
- grid.13291.380000 0001 0807 1581State Key Laboratory of Biotherapy and Cancer Center, Department of Laboratory Medicine, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 China
| | - Chengyali Liu
- grid.13291.380000 0001 0807 1581State Key Laboratory of Biotherapy and Cancer Center, Department of Laboratory Medicine, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 China
| | - Yuanwei Chen
- Hinova Pharmaceuticals Inc., Chengdu, 610041 China
| | - Lei Fan
- Hinova Pharmaceuticals Inc., Chengdu, 610041 China
| | - Hongqun Ma
- Hinova Pharmaceuticals Inc., Chengdu, 610041 China
| | - Youling Gong
- grid.13291.380000 0001 0807 1581Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Yongmei Xie
- grid.13291.380000 0001 0807 1581State Key Laboratory of Biotherapy and Cancer Center, Department of Laboratory Medicine, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 China
| |
Collapse
|
|
32
|
Jin J, Wu Y, Zhao Z, Wu Y, Zhou YD, Liu S, Sun Q, Yang G, Lin J, Nagle DG, Qin J, Zhang Z, Chen HZ, Zhang W, Sun S, Luan X. Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer. JCI Insight 2022; 7:160606. [PMID: 36509291 DOI: 10.1172/jci.insight.160606] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 10/11/2022] [Indexed: 11/22/2022] Open
Abstract
The aberrant activation of STAT3 is associated with the etiology and progression in a variety of malignant epithelial-derived tumors, including head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). Due to the lack of an enzymatic catalytic site or a ligand-binding pocket, there are no small-molecule inhibitors directly targeting STAT3 that have been approved for clinical translation. Emerging proteolysis targeting chimeric (PROTAC) technology-based approach represents a potential strategy to overcome the limitations of conventional inhibitors and inhibit activation of STAT3 and downstream genes. In this study, the heterobifunctional small-molecule-based PROTACs are successfully prepared from toosendanin (TSN), with 1 portion binding to STAT3 and the other portion binding to an E3 ubiquitin ligase. The optimized lead PROTAC (TSM-1) exhibits superior selectivity, potency, and robust antitumor effects in STAT3-dependent HNSCC and CRC - especially in clinically relevant patient-derived xenografts (PDX) and patient-derived organoids (PDO). The following mechanistic investigation identifies the reduced expression of critical downstream STAT3 effectors, through which TSM-1 promotes cell cycle arrest and apoptosis in tumor cells. These findings provide the first demonstration to our knowledge of a successful PROTAC-targeting strategy in STAT3-dependent epithelial cancer.
Collapse
Affiliation(s)
- Jinmei Jin
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yaping Wu
- Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and.,National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Zeng Zhao
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.,China Institute of Pharmaceutical Industry, Shanghai, China
| | - Ye Wu
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu-Dong Zhou
- Department of Chemistry and Biochemistry, College of Liberal Arts, and
| | - Sanhong Liu
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qingyan Sun
- China Institute of Pharmaceutical Industry, Shanghai, China
| | - Guizhu Yang
- Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and.,National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Jiayi Lin
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dale G Nagle
- Department of Chemistry and Biochemistry, College of Liberal Arts, and.,Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA
| | - Jiangjiang Qin
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Zhiyuan Zhang
- Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and.,National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Hong-Zhuan Chen
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weidong Zhang
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shuyang Sun
- Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and.,National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Xin Luan
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
33
|
Conioselinum tenuissimum Root Extract Modulates Macrophage Activation via the Calcium–STAT3 Pathway. Processes (Basel) 2022. [DOI: 10.3390/pr10112238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Despite the development of many antibiotics, excessive inflammation caused by endotoxins is still a subject of interest to biomedical researchers. The hyper-inflammatory response of macrophages activated by endotoxins is an important topic in the development of natural product-based anti-inflammatory drugs. Conioselinum tenuissimum, a perennial herb of the family Apiaceae, contains levistolide A, demethylsuberosin, and fraxetin. One of the synonyms of Conioselinum tenuissimum is Angelica tenuissima. The objective of this study was to determine the effects of Conioselinumtenuissimum root water extract (AT) on the hyper-inflammatory responses of macrophages activated by endotoxin (lipopolysaccharide; LPS) and the mechanisms involved in such effects. Levels of cytokines, nitric oxide (NO), hydrogen peroxide, and cytosolic calcium in LPS-activated RAW 264.7 murine macrophages were evaluated by the multiplex cytokine assay (MCA), Griess reagent assay (GRA), dihydrorhodamine 123 assay (DHR), and Fluo-4 calcium assay (FCA), respectively. Additionally, real-time PCR and the flow cytometry assay (FLA) was performed to determine the effects of AT on LPS-activated RAW 264.7. Data from MCA, GRA, DHR, and FCA revealed that AT lowered levels of IL-6, MCP-1, TNF-α, G-CSF, GM-CSF, VEGF, M-CSF, LIF, LIX, MIP-1α, MIP-1β, MIP-2, RANTES, IP-10, NO, hydrogen peroxide, and calcium in LPS-activated RAW 264.7. Real-time PCR results revealed that AT significantly lowered mRNA expression levels of inflammatory genes such as Chop, Nos2, c-Jun, Stat1, Stat3, c-Fos, Camk2a, Ptgs2, Fas, and Jak2. FLA showed that AT significantly reduced phosphorylation levels of P38 MAPK and STAT3 in LPS-activated RAW 264.7. These results indicate that AT can exert anti-inflammatory effects in LPS-activated macrophages via the calcium–STAT3 pathway.
Collapse
|
|
34
|
Recent Advances in PROTACs for Drug Targeted Protein Research. Int J Mol Sci 2022; 23:ijms231810328. [PMID: 36142231 PMCID: PMC9499226 DOI: 10.3390/ijms231810328] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 01/30/2023] Open
Abstract
Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule. Typically, PROTAC consists of two terminals which are the ligand of the protein of interest (POI) and the specific ligand of E3 ubiquitin ligase, respectively, via a suitable linker. PROTAC degradation of the target protein is performed through the ubiquitin–proteasome system (UPS). The general process is that PROTAC binds to the target protein and E3 ligase to form a ternary complex and label the target protein with ubiquitination. The ubiquitinated protein is recognized and degraded by the proteasome in the cell. At present, PROTAC, as a new type of drug, has been developed to degrade a variety of cancer target proteins and other disease target proteins, and has shown good curative effects on a variety of diseases. For example, PROTACs targeting AR, BR, BTK, Tau, IRAK4, and other proteins have shown unprecedented clinical efficacy in cancers, neurodegenerative diseases, inflammations, and other fields. Recently, PROTAC has entered a phase of rapid development, opening a new field for biomedical research and development. This paper reviews the various fields of targeted protein degradation by PROTAC in recent years and summarizes and prospects the hot targets and indications of PROTAC.
Collapse
|
|
35
|
Regulation of NFKBIZ gene promoter activity by STAT3, C/EBPβ, and STAT1. Biochem Biophys Res Commun 2022; 613:61-66. [DOI: 10.1016/j.bbrc.2022.04.140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 04/30/2022] [Indexed: 11/30/2022]
|
|
36
|
Mukvich OM, Telegeev GD, Matskevych AM, Gilfanova AM. Polymorphisms of Genes Associated with Intracellular Signaling Pathways in Juvenile Idiopathic Arthritis. CYTOL GENET+ 2022. [DOI: 10.3103/s0095452722030070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
37
|
Hong YK, Wu CH, Lin YC, Huang YL, Hung KS, Pai TP, Liu YT, Chen TC, Chan H, Hsu CK. ASC-J9 Blocks Cell Proliferation and Extracellular Matrix Production of Keloid Fibroblasts through Inhibiting STAT3 Signaling. Int J Mol Sci 2022; 23:ijms23105549. [PMID: 35628356 PMCID: PMC9141592 DOI: 10.3390/ijms23105549] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/10/2022] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
Keloids are a fibrotic skin disorder caused by abnormal wound healing and featuring the activation and expansion of fibroblasts beyond the original wound margin. Signal transducer and activator of transcription 3 (STAT3) has been found to mediate the biological functions of keloid fibroblasts (KFs). Therefore, we aimed to demonstrate whether ASC-J9, an inhibitor of STAT3 phosphorylation, can suppress the activation of KFs. Western blotting results showed that ASC-J9 inhibited the levels of COL1A1 and FN1 proteins, which were upregulated in KFs, by decreasing the expression of pSTAT3 and STAT3. RNA sequencing and in vitro studies further demonstrated that ASC-J9 treatment of KFs reduced cell division, inflammation, and ROS generation, as well as extracellular matrix (ECM) synthesis. ELISA assays verified that ASC-J9 treatment significantly mitigated IL-6 protein secretion in KFs. Transmission electron microscopy images revealed that ASC-J9 induced the formation of multilamellar bodies in KFs, which is associated with autophagy-related signaling. These results suggested that inhibiting a vicious cycle of the ROS/STAT3/IL-6 axis by ASC-J9 may represent a potential therapeutic approach to suppress cell proliferation and ECM production in KFs.
Collapse
Affiliation(s)
- Yi-Kai Hong
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; (Y.-K.H.); (Y.-C.L.); (Y.-L.H.)
- International Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan 701, Taiwan
| | - Chen-Han Wu
- Allianz Pharmascience, Ltd. (Now AnnJi Pharmaceutical, Co., Ltd.), Taipei 100, Taiwan; (C.-H.W.); (T.-P.P.); (Y.-T.L.); (T.-C.C.); (H.C.)
| | - Yu-Chen Lin
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; (Y.-K.H.); (Y.-C.L.); (Y.-L.H.)
- International Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan 701, Taiwan
| | - Yu-Lun Huang
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; (Y.-K.H.); (Y.-C.L.); (Y.-L.H.)
| | - Kuo-Shu Hung
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
| | - Tsung-Pin Pai
- Allianz Pharmascience, Ltd. (Now AnnJi Pharmaceutical, Co., Ltd.), Taipei 100, Taiwan; (C.-H.W.); (T.-P.P.); (Y.-T.L.); (T.-C.C.); (H.C.)
| | - Yen-Ting Liu
- Allianz Pharmascience, Ltd. (Now AnnJi Pharmaceutical, Co., Ltd.), Taipei 100, Taiwan; (C.-H.W.); (T.-P.P.); (Y.-T.L.); (T.-C.C.); (H.C.)
| | - Tzu-Chi Chen
- Allianz Pharmascience, Ltd. (Now AnnJi Pharmaceutical, Co., Ltd.), Taipei 100, Taiwan; (C.-H.W.); (T.-P.P.); (Y.-T.L.); (T.-C.C.); (H.C.)
| | - Hardy Chan
- Allianz Pharmascience, Ltd. (Now AnnJi Pharmaceutical, Co., Ltd.), Taipei 100, Taiwan; (C.-H.W.); (T.-P.P.); (Y.-T.L.); (T.-C.C.); (H.C.)
| | - Chao-Kai Hsu
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; (Y.-K.H.); (Y.-C.L.); (Y.-L.H.)
- International Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan 701, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- Correspondence: ; Tel.: +886-6-2353535-5415
| |
Collapse
|
|
38
|
STAT3 Role in T-Cell Memory Formation. Int J Mol Sci 2022; 23:ijms23052878. [PMID: 35270020 PMCID: PMC8910982 DOI: 10.3390/ijms23052878] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/12/2022] Open
Abstract
Along with the clinical success of immuno-oncology drugs and cellular therapies, T-cell biology has attracted considerable attention in the immunology community. Long-term immunity, traditionally analyzed in the context of infection, is increasingly studied in cancer. Many signaling pathways, transcription factors, and metabolic regulators have been shown to participate in the formation of memory T cells. There is increasing evidence that the signal transducer and activator of transcription-3 (STAT3) signaling pathway is crucial for the formation of long-term T-cell immunity capable of efficient recall responses. In this review, we summarize what is currently known about STAT3 role in the context of memory T-cell formation and antitumor immunity.
Collapse
|
|
39
|
Expression and prognostic analysis of STAT6(YE361) in Hodgkin lymphoma. Pathol Res Pract 2022; 231:153781. [DOI: 10.1016/j.prp.2022.153781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 01/19/2022] [Accepted: 01/22/2022] [Indexed: 01/10/2023]
|
|
40
|
Myers SA, Gottschalk RA. Mechanisms encoding STAT functional diversity for context-specific inflammatory responses. Curr Opin Immunol 2022; 74:150-155. [DOI: 10.1016/j.coi.2022.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 01/22/2023]
|
|
41
|
Verweyen EL, Schulert GS. Interfering with interferons: targeting the JAK-STAT pathway in complications of systemic juvenile idiopathic arthritis (SJIA). Rheumatology (Oxford) 2021; 61:926-935. [PMID: 34459891 PMCID: PMC9123899 DOI: 10.1093/rheumatology/keab673] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/27/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Systemic JIA (SJIA) is distinguished from other forms of JIA by the prevalence of the severe, life-threatening complications macrophage activation syndrome (SJIA-MAS) and lung disease (SJIA-LD). Alternative therapeutics are urgently needed, as disease pathogenesis diverges from what is observed in SJIA, and currently available biologics are insufficient. SJIA-MAS, defined by a cytokine storm and dysregulated proliferation of T-lymphocytes, and SJIA-LD which presents with lymphocytic interstitial inflammation and pulmonary alveolar proteinosis, are both thought to be driven by IFNs, in particular the type II IFN-γ. Involvement of IFNs and a possible crosstalk of type I IFNs with existing biologics indicate a distinct role for the JAK-STAT signalling pathway in the pathogenesis of SJIA-MAS and SJIA-LD. Here, we review this role of JAK-STATs and IFNs in SJIA complications and discuss how new insights of ongoing research are shaping future therapeutic advances in the form of JAK inhibitors and antibodies targeting IFNs.
Collapse
Affiliation(s)
- Emely L Verweyen
- Division of Rheumatology, Cincinnati Children's Hospital Medical Center
| | - Grant S Schulert
- Division of Rheumatology, Cincinnati Children's Hospital Medical Center,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA,Correspondence to: Grant Schulert, Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, MLC 4010, 3333 Burnet Avenue, Cincinnati, OH 45208, USA.
E-mail:
| |
Collapse
|
|
42
|
Cho K, Lee HG, Piao JY, Kim SJ, Na HK, Surh YJ. Protective Effects of Silibinin on Helicobacter pylori-induced Gastritis: NF-κB and STAT3 as Potential Targets. J Cancer Prev 2021; 26:118-127. [PMID: 34258250 PMCID: PMC8249208 DOI: 10.15430/jcp.2021.26.2.118] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/24/2021] [Accepted: 02/24/2021] [Indexed: 12/25/2022] Open
Abstract
More than half of the world's populations are considered to be infected by Helicobacter pylori. It causes a chronic inflammation of the stomach, which is implicated in the pathogenesis of gastric ulcer and cancer. Silibinin, a polyphenolic flavonoid derived from milk thistle, has been known for its hepatoprotective effects, and recent studies have revealed its chemopreventive potential. In the present study, we examined the anti-inflammatory effects of silibinin in human gastric cancer MKN-1 cells and in the stomach of C57BL/6 mice infected by H. pylori. Pretreatment with silibinin attenuated the up-regulation of COX-2 and inducible nitric oxide synthase (iNOS) in H. pylori-infected MKN-1 cells and mouse stomach. In addition, the elevated translocation and DNA binding of NF-κB and STAT3 induced by H. pylori infection were inhibited by silibinin treatment. Moreover, H. pylori infection in combination with high salt diet resulted in dysplasia and hyperplasia in mouse stomach, and these pathological manifestations were substantially mitigated by silibinin administration. Taken together, these findings suggest that silibinin exerts anti-inflammatory effects against H. pylori infection through suppression of NF-κB and STAT3 and subsequently, expression of COX-2 and iNOS.
Collapse
Affiliation(s)
- Kyunghwa Cho
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Hee Geum Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Juan-Yu Piao
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Su-Jung Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, College of Knowledge-based Services Engineering, Sungshin Women's University, Seoul, Korea
| | - Young-Joon Surh
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea
| |
Collapse
|
|
43
|
Woock AE, Grible JM, Olex AL, Harrell JC, Zot P, Idowu M, Clevenger CV. Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer. Sci Rep 2021; 11:13506. [PMID: 34188118 PMCID: PMC8242097 DOI: 10.1038/s41598-021-92830-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/11/2021] [Indexed: 01/19/2023] Open
Abstract
In breast cancer, prolactin-induced activation of the transcription factor STAT5a results from the phosphorylation of STAT5a tyrosine residue 694. However, its role in mammary oncogenesis remains an unsettled debate as STAT5a exhibits functional dichotomy with both pro-differentiative and pro-proliferative target genes. Phosphorylation of STAT5a serine residues, S726 and S780, may regulate STAT5a in such a way to underlie this duality. Given hematopoiesis studies showing phospho-serine STAT5a as necessary for transformation, we hypothesized that serine phosphorylation regulates STAT5a activity to contribute to its role in mammary oncogenesis, specifically in luminal breast cancer. Here, phosphorylation of S726-, S780-, and Y694-STAT5a in response to prolactin in MCF7 luminal breast cancer cells was investigated with STAT5a knockdown and rescue with Y694F-, S726A-, or S780A-STAT5a, where the phospho-sites were mutated. RNA-sequencing and subsequent Ingenuity Pathway Analysis predicted that loss of each phospho-site differentially affected both prolactin-induced gene expression as well as functional pathways of breast cancer (e.g. cell survival, proliferation, and colony formation). In vitro studies of anchorage-independent growth and proliferation confirmed distinct phenotypes: whereas S780A-STAT5a decreased clonogenicity, S726A-STAT5a decreased proliferation in response to prolactin compared to wild type STAT5a. Collectively, these studies provide novel insights into STAT5a activation in breast cancer pathogenesis.
Collapse
Affiliation(s)
- Alicia E Woock
- Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall St, Sanger 4-006A, Richmond, VA, 23298-06629, USA
| | - Jacqueline M Grible
- Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall St, Sanger 4-006A, Richmond, VA, 23298-06629, USA
| | - Amy L Olex
- C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - J Chuck Harrell
- Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall St, Sanger 4-006A, Richmond, VA, 23298-06629, USA
| | - Patricija Zot
- Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall St, Sanger 4-006A, Richmond, VA, 23298-06629, USA
| | - Michael Idowu
- Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall St, Sanger 4-006A, Richmond, VA, 23298-06629, USA
| | - Charles V Clevenger
- Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall St, Sanger 4-006A, Richmond, VA, 23298-06629, USA.
| |
Collapse
|
|
44
|
Targeting Canonical and Non-Canonical STAT Signaling Pathways in Renal Diseases. Cells 2021; 10:cells10071610. [PMID: 34199002 PMCID: PMC8305338 DOI: 10.3390/cells10071610] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/16/2021] [Accepted: 06/22/2021] [Indexed: 01/05/2023] Open
Abstract
Signal transducer and activator of transcription (STAT) plays an essential role in the inflammatory reaction and immune response of numerous renal diseases. STATs can transmit the signals of cytokines, chemokines, and growth factors from the cell membrane to the nucleus. In the canonical STAT signaling pathways, upon binding with their cognate receptors, cytokines lead to a caspase of Janus kinases (JAKs) and STATs tyrosine phosphorylation and activation. Besides receptor-associated tyrosine kinases JAKs, receptors with intrinsic tyrosine kinase activities, G-protein coupled receptors, and non-receptor tyrosine kinases can also activate STATs through tyrosine phosphorylation or, alternatively, other post-translational modifications. Activated STATs translocate into the nucleus and mediate the transcription of specific genes, thus mediating the progression of various renal diseases. Non-canonical STAT pathways consist of preassembled receptor complexes, preformed STAT dimers, unphosphorylated STATs (U-STATs), and non-canonical functions including mitochondria modulation, microtubule regulation and heterochromatin stabilization. Most studies targeting STAT signaling pathways have focused on canonical pathways, but research extending into non-canonical STAT pathways would provide novel strategies for treating renal diseases. In this review, we will introduce both canonical and non-canonical STAT pathways and their roles in a variety of renal diseases.
Collapse
|
|
45
|
Zhou H, Bai L, Xu R, McEachern D, Chinnaswamy K, Li R, Wen B, Wang M, Yang CY, Meagher JL, Sun D, Stuckey JA, Wang S. SD-91 as A Potent and Selective STAT3 Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression. ACS Med Chem Lett 2021; 12:996-1004. [PMID: 34141084 DOI: 10.1021/acsmedchemlett.1c00155] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/05/2021] [Indexed: 11/30/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. We report herein our extensive in vitro and in vivo evaluations of SD-91, the product of the hydrolysis of our previously reported STAT3 degrader SD-36. SD-91 binds to STAT3 protein with a high affinity and displays >300-fold selectivity over other STAT family protein members. SD-91 potently and effectively induces degradation of STAT3 protein and displays a high selectivity over other STAT members and >7000 non-STAT proteins in cells. A single administration of SD-91 selectively depletes STAT3 protein in tumor tissues with a persistent effect. SD-91 achieves complete and long-lasting tumor regression in the MOLM-16 xenograft model in mice even with weekly administration. Hence, SD-91 is a potent, highly selective, and efficacious STAT3 degrader for extensive evaluations for the treatment of human cancers and other diseases for which STAT3 plays a key role.
Collapse
|
|
46
|
Hu Y, Liu F, Jia X, Wang P, Gu T, Liu H, Liu T, Wei H, Chen H, Zhao J, Yang R, Chen Y, Dong Z, Liu K. Periplogenin suppresses the growth of esophageal squamous cell carcinoma in vitro and in vivo by targeting STAT3. Oncogene 2021; 40:3942-3958. [PMID: 33986510 DOI: 10.1038/s41388-021-01817-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 04/03/2021] [Accepted: 04/23/2021] [Indexed: 02/07/2023]
Abstract
The mortality rate of esophageal squamous cell carcinoma (ESCC) is higher than that of other cancers worldwide owing to a lack of therapeutic targets and related drugs. This study aimed to find new drugs by targeting an efficacious therapeutic target in ESCC patients. Signal transducer and activator of transcription 3 (STAT3) is hyperactive in ESCC. Herein, we identified a novel STAT3 inhibitor, periplogenin, which strongly inhibited phosphorylation of STAT3 at Tyr705. Docking models and pull-down assays revealed that periplogenin bound directly and specifically to STAT3, leading to significant suppression of subsequent dimerization, nuclear import, and transcription activities. In addition, STAT3 knockdown cell lines were insensitive to periplogenin, whereas in contrast, STAT3-overexpressing cells were more sensitive to periplogenin, indicating that STAT3 was a target of periplogenin. Intraperitoneally administered periplogenin exhibited efficacious therapeutic effects in ESCC patient-derived xenograft models and dramatically impaired the phosphorylation of STAT3 and expression levels of STAT3-mediated downstream genes. Thus, our study demonstrated that periplogenin acted as a new STAT3 inhibitor, suppressing the growth of ESCC in vitro and in vivo, providing a basis for its potential application in ESCC treatment and prevention.
Collapse
Affiliation(s)
- Yamei Hu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Fangfang Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Xuechao Jia
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Penglei Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Tingxuan Gu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Hui Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Tingting Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Huifang Wei
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Hanyong Chen
- The Hormel Institute, University of Minnesota, Austin, MN55912, USA
| | - Jiuzhou Zhao
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, 450008, China
| | - Ran Yang
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Yingying Chen
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China.
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, China.
- Cancer chemoprevention international collaboration laboratory, Zhengzhou, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China.
| |
Collapse
|
|
47
|
Bond MJ, Crews CM. Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. RSC Chem Biol 2021; 2:725-742. [PMID: 34212149 PMCID: PMC8190915 DOI: 10.1039/d1cb00011j] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
With the discovery of PROteolysis TArgeting Chimeras (PROTACs) twenty years ago, targeted protein degradation (TPD) has changed the landscape of drug development. PROTACs have evolved from cell-impermeable peptide-small molecule chimeras to orally bioavailable clinical candidate drugs that degrade oncogenic proteins in humans. As we move into the third decade of TPD, the pace of discovery will only accelerate. Improved technologies are enabling the development of ligands for "undruggable" proteins and the recruitment of new E3 ligases. Moreover, enhanced computing power will expedite identification of active degraders. Here we discuss the strides made in these areas and what advances we can look forward to as the next decade in this exciting field begins.
Collapse
Affiliation(s)
- Michael J Bond
- Department of Pharmacology, Yale University New Haven CT 06511 USA
| | - Craig M Crews
- Department of Pharmacology, Yale University New Haven CT 06511 USA
- Department of Molecular, Cellular, and Developmental Biology, Yale University New Haven CT 06511 USA
- Department of Chemistry, Yale University New Haven CT 06511 USA
| |
Collapse
|
|
48
|
Han Y, Zhang J, Huang S, Cheng N, Zhang C, Li Y, Wang X, Liu J, You B, Du J. MicroRNA-223-3p inhibits vascular calcification and the osteogenic switch of vascular smooth muscle cells. J Biol Chem 2021; 296:100483. [PMID: 33647318 PMCID: PMC8039724 DOI: 10.1016/j.jbc.2021.100483] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 02/19/2021] [Accepted: 02/25/2021] [Indexed: 11/20/2022] Open
Abstract
Vascular calcification is the ectopic deposition of calcium hydroxyapatite minerals in arterial wall, which involves the transdifferentiation of vascular smooth muscle cells (VSMCs) toward an osteogenic phenotype. However, the underlying molecular mechanisms regulating the VSMC osteogenic switch remain incompletely understood. In this study, we examined the roles of microRNAs (miRNAs) in vascular calcification. miRNA-seq transcriptome analysis identified miR-223-3p as a candidate miRNA in calcified mouse aortas. MiR-223-3p knockout aggravated calcification in both medial and atherosclerotic vascular calcification models. Further, RNA-seq transcriptome analysis verified JAK-STAT and PPAR signaling pathways were upregulated in both medial and atherosclerotic calcified aortas. Overlapping genes in these signaling pathways with predicted target genes of miR-223-3p derived from miRNA databases, we identified signal transducer and activator of transcription 3 (STAT3) as a potential target gene of miR-223-3p in vascular calcification. In vitro experiments showed that miR-223-3p blocked interleukin-6 (IL-6)/STAT3 signaling, thereby preventing the osteogenic switch and calcification of VSMCs. In contrast, overexpression of STAT3 diminished the effect of miR-223-3p. Taken together, the results indicate a protective role of miR-223-3p that inhibits both medial and atherosclerotic vascular calcification by regulating IL-6/STAT3 signaling-mediated VSMC transdifferentiation.
Collapse
Affiliation(s)
- Yingchun Han
- Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Jichao Zhang
- Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Shan Huang
- Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China; School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Naixuan Cheng
- Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China; School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Congcong Zhang
- Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Yulin Li
- Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Xiaonan Wang
- Renal Division, Department of Medicine, Emory University, Atlanta, Georgia, USA
| | - Jinghua Liu
- Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Bin You
- Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
| | - Jie Du
- Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
| |
Collapse
|
|
49
|
Andrieux G, Chakraborty S, Das T, Boerries M. Alteration of Proteotranscriptomic Landscape Reveals the Transcriptional Regulatory Circuits Controlling Key-Signaling Pathways and Metabolic Reprogramming During Tumor Evolution. Front Cell Dev Biol 2021; 8:586479. [PMID: 33384992 PMCID: PMC7769845 DOI: 10.3389/fcell.2020.586479] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 11/20/2020] [Indexed: 11/15/2022] Open
Abstract
The proteotranscriptomic landscape depends on the transcription, mRNA-turnover, translation, and regulated-destruction of proteins. Gene-specific mRNA-to-protein correlation is the consequence of the dynamic interplays of the different regulatory processes of proteotranscriptomic landscape. So far, the critical impact of mRNA and protein stability on their subsequent correlation on a global scale remained unresolved. Whether the mRNA-to-protein correlations are constrained by their stability and conserved across mammalian species including human is unknown. Moreover, whether the stability-dependent correlation pattern is altered in the tumor has not been explored. To establish the quantitative relationship between stability and correlation between mRNA and protein levels, we performed a multi-omics data integration study across mammalian systems including diverse types of human tissues and cell lines in a genome-wide manner. The current study illuminated an important aspect of the mammalian proteotranscriptomic landscape by providing evidence that stability-constrained mRNA-to-protein correlation follows a hierarchical pattern that remains conserved across different tissues and mammalian species. By analyzing the tumor and non-tumor tissues, we further illustrated that mRNA-to-protein correlations deviate in tumor tissues. By gene-centric analysis, we harnessed the hierarchical correlation patterns to identify altered mRNA-to-protein correlation in tumors and characterized the tumor correlation-enhancing and -repressing genes. We elucidated the transcriptional regulatory circuits controlling the correlation-enhancing and -repressing genes that are associated with metabolic reprogramming and cancer-associated pathways in tumor tissue. By tightly controlling the mRNA-to-protein correlation of specific genes, the transcriptional regulatory circuits may enable the tumor cells to evolve in varying tumor microenvironment. The mRNA-to-protein correlation analysis thus can serve as a unique approach to identify the pathways prioritized by the tumor cells at different clinical stages. The component of transcriptional regulatory circuits identified by the current study can serve as potential candidates for stage-dependent anticancer therapy.
Collapse
Affiliation(s)
- Geoffroy Andrieux
- Faculty of Medicine, Medical Center-University of Freiburg, Institute of Medical Bioinformatics and Systems Medicine, University of Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sajib Chakraborty
- Molecular Systems Biology Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Tonmoy Das
- Molecular Systems Biology Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Melanie Boerries
- Faculty of Medicine, Medical Center-University of Freiburg, Institute of Medical Bioinformatics and Systems Medicine, University of Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany
| |
Collapse
|
|
50
|
Cao Y, Fang T, Fan M, Wang L, Lv C, Jin P, Ma F. Functional characterization of STATa/b genes encoding transcription factors from Branchiostoma belcheri. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 114:103838. [PMID: 32846160 DOI: 10.1016/j.dci.2020.103838] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 06/11/2023]
Abstract
The signal transducer and activator of transcription (STAT), as an important transcription factor of the Janus kinase (JAK)-STAT signaling pathway, is pivotal for development and immunity and well documented in vertebrates. However, the STAT gene has not been reported in chordate amphioxus (Branchiostoma belcheri). In this study, we firstly identify and characterize two STAT genes from Branchiostoma belcheri (designed as AmphiSTATa and AmphiSTATb). Secondly, our results reveal that AmphiSTATa is clustered with vertebrate STAT1, STAT2, STAT3 and STAT4, whereas AmphiSTATb is grouped with STAT5 and STAT6 based on phylogenetic analysis. Thirdly, AmphiSTATa and AmphiSTATb are found to widely express in five representative tissues of amphioxus (gill, hepatic cecum, intestine, muscle and notochord) by RT-qPCR analysis. Importantly, both AmphiSTATa and AmphiSTATb can be involved in innate immune responses to LPS stimulation. Fourthly, we demonstrate that AmphiSTATa and AmphiSTATb can form homodimers or heterodimers by Co-IP and Native-PAGE assay, and that AmphiSTATa and AmphiSTATb proteins can also distribute in cytoplasm and nucleus by the subcellular localization. Taken together, our findings not only reveal the roles of AmphiSTATa and AmphiSTATb in amphioxus innate immune responses to LPS stimulation, but provide a new insight into further elucidating the evolution and function of STATs in animals.
Collapse
Affiliation(s)
- Yunpeng Cao
- Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, China
| | - Tao Fang
- Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, China
| | - Mingli Fan
- Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, China
| | - Lei Wang
- Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, China
| | - Caiyun Lv
- Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, China
| | - Ping Jin
- Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, China.
| | - Fei Ma
- Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, China.
| |
Collapse
|