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Chen J, Li M, Mao J, Wang X, Guo B, Chen X, Kalvakolanu DV, Hong J, Yang M, Liu J, Luo Q, Yang J, Sun X, Tian Y, Zhang L. Transglutaminase 2 promotes breast cancer cell autophagy by targeting p53/ mTOR axis. Biochem Pharmacol 2025; 237:116926. [PMID: 40216264 DOI: 10.1016/j.bcp.2025.116926] [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: 01/08/2025] [Revised: 03/22/2025] [Accepted: 04/02/2025] [Indexed: 04/19/2025]
Abstract
Breast cancer (BC) is the most common malignant tumor among women. There is a pressing demand to develop new therapeutic strategies for advanced BC. In this report, we investigated whether Transglutaminase 2 (TGM2) is involved in BC growth. Moreover, a high expression of TGM2 in BC was found to be correlated with a poor prognosis. Thus, TGM2 might be a prospective therapeutic target in BC. We examined if a small molecule inhibitor of TGM2, GK921, could suppress BC growth. GK921 inhibited TGM2 activity and induced autophagy-dependent cell death in BC cell lines. Additionally, we found that GK921 increased p53 levels, which decreased the expression of mTOR, a classical upstream regulator of autophagy. Finally, we found that down regulation of TGM2 using RNAi activated autophagy. Consistent with these findings, GK921 significantly suppressed breast tumor growth in mouse models, suggesting that TGM2 may be a potential therapeutic target for BC treatment.
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Affiliation(s)
- Jiasi Chen
- College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, Jilin University, Changchun 130021, China
| | - Mengxin Li
- Department of Breast Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, China
| | - Juanjuan Mao
- College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, Jilin University, Changchun 130021, China
| | - Xuanzhong Wang
- Department of Radiation Oncology, First Hospital of Jilin University, Changchun, China
| | - Baofeng Guo
- Department of Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xuyang Chen
- School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Dhan V Kalvakolanu
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jinghui Hong
- Department of Breast Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, China
| | - Mei Yang
- College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, Jilin University, Changchun 130021, China
| | - Jixuan Liu
- College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, Jilin University, Changchun 130021, China
| | - Qian Luo
- College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, Jilin University, Changchun 130021, China
| | - Jiaying Yang
- College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, Jilin University, Changchun 130021, China
| | - Xinze Sun
- College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, Jilin University, Changchun 130021, China
| | - Yong Tian
- College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, Jilin University, Changchun 130021, China
| | - Ling Zhang
- College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, Jilin University, Changchun 130021, China.
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Jia H, Wei J, Zheng W, Li Z. The dual role of autophagy in cancer stem cells: implications for tumor progression and therapy resistance. J Transl Med 2025; 23:583. [PMID: 40414839 DOI: 10.1186/s12967-025-06595-z] [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: 02/24/2025] [Accepted: 05/08/2025] [Indexed: 05/27/2025] Open
Abstract
Cancer stem cells (CSCs) constitute a small yet crucial subgroup in tumors, known for their capacity to self-renew, differentiate, and promote tumor growth, metastasis, and resistance to therapy. These characteristics position CSCs as significant factors in tumor recurrence and unfavorable clinical results, emphasizing their role as targets for therapy. Autophagy, an evolutionarily preserved cellular mechanism for degradation and recycling, has a complex function in cancer by aiding cell survival during stress and preserving balance by eliminating damaged organelles and proteins. Although autophagy can hinder tumor growth by reducing genomic instability, it also aids tumor advancement, particularly in harsh microenvironments, highlighting its dual characteristics. Recent research has highlighted the complex interactions between autophagy and CSCs, showing that autophagy governs CSC maintenance, boosts survival, and aids in resistance to chemotherapy and radiotherapy. On the other hand, in specific situations, autophagy may restrict CSC growth by increasing differentiation or inducing cell death. These intricate interactions offer both obstacles and possibilities for therapeutic intervention. Pharmacological modulation of autophagy, via inhibitors like chloroquine or by enhancing autophagy when advantageous, has demonstrated potential in making CSCs more responsive to standard treatments. Nonetheless, applying these strategies in clinical settings necessitates a better understanding of context-dependent autophagy dynamics and the discovery of dependable biomarkers indicating autophagic activity in CSCs. Progressing in this area might unveil novel, accurate strategies to tackle therapy resistance, lessen tumor recurrence, and ultimately enhance patient outcomes.
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Affiliation(s)
- Haiqing Jia
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China
| | - Jing Wei
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China
| | - Wei Zheng
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China.
| | - Zhuo Li
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China.
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Huang X, Yan H, Xu Z, Yang B, Luo P, He Q. The inducible role of autophagy in cell death: emerging evidence and future perspectives. Cell Commun Signal 2025; 23:151. [PMID: 40140912 PMCID: PMC11948861 DOI: 10.1186/s12964-025-02135-w] [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: 12/08/2024] [Accepted: 03/02/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Autophagy is a lysosome-dependent degradation pathway for recycling intracellular materials and removing damaged organelles, and it is usually considered a prosurvival process in response to stress stimuli. However, increasing evidence suggests that autophagy can also drive cell death in a context-dependent manner. The bulk degradation of cell contents and the accumulation of autophagosomes are recognized as the mechanisms of cell death induced by autophagy alone. However, autophagy can also drive other forms of regulated cell death (RCD) whose mechanisms are not related to excessive autophagic vacuolization. Notably, few reviews address studies on the transformation from autophagy to RCD, and the underlying molecular mechanisms are still vague. AIM OF REVIEW This review aims to summarize the existing studies on autophagy-mediated RCD, to elucidate the mechanism by which autophagy initiates RCD, and to comprehensively understand the role of autophagy in determining cell fate. KEY SCIENTIFIC CONCEPTS OF REVIEW This review highlights the prodeath effect of autophagy, which is distinct from the generally perceived cytoprotective role, and its mechanisms are mainly associated with the selective degradation of proteins or organelles essential for cell survival and the direct involvement of the autophagy machinery in cell death. Additionally, this review highlights the need for better manipulation of autophagy activation or inhibition in different pathological contexts, depending on clinical purpose.
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Affiliation(s)
- Xiangliang Huang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- School of Medicine, Hangzhou City University, Hangzhou, 310015, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China.
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- School of Medicine, Hangzhou City University, Hangzhou, 310015, China.
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China.
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Tjahjono E, Daneman MR, Meika B, Revtovich AV, Kirienko NV. Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia. Front Oncol 2025; 14:1532857. [PMID: 39902131 PMCID: PMC11788353 DOI: 10.3389/fonc.2024.1532857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 12/27/2024] [Indexed: 02/05/2025] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy; it is the most common acute leukemia in adults. AML prognosis is often poor, and relapse often occurs after initial remission. Recurrent genetic abnormalities underlying this disease and the presence of leukemic stem cells complicate disease treatment. However, the complex metabolic reprogramming that enables the unrestrained cell growth seen in these cells may also be their Achilles' heel. In these cells, mitophagy operates as a double-edged sword. On one hand, it provides a source of building blocks for further cell division and serves as a method for removing damaged organelles, promoting cell survival. However, the profound metabolic changes to mitochondria also render these organelles more sensitive to damage and place them precariously close to excess mitophagic activation. This review discusses the dual role mitophagy plays in AML survival, the importance of targeting mitophagy to treat AML, and current progress in the area. The discovery and mechanism of action of multiple compounds that were used to inhibit or stimulate mitophagy and their effects on AML survival are also described. Further, we explore the combination strategy of mitophagy-targeting compounds with existing and/or novel chemotherapeutics to eradicate AML and discuss strategies to uncover new drug targets and novel mitochondria-targeting drugs.
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Mao C, Zhang J, Yang C, Mei L, Feng Y, Dai F, Huang Y, Xiao H, Deng B. BCAR1 facilitates the survival of lung adenocarcinoma cells by augmenting the unfolded protein response, autophagy, and the formation of vasculogenic mimicry. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167558. [PMID: 39488300 DOI: 10.1016/j.bbadis.2024.167558] [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: 03/29/2024] [Revised: 10/23/2024] [Accepted: 10/28/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Our objective was to elucidate the pivotal roles of BCAR1 in unfolded protein response (UPR), autophagy and vasculogenic mimicry (VM) formation, processes that essential for the metastasis of lung adenocarcinoma (LUAD) cells. METHODS The morphological assessment of endoplasmic reticulum (ER) status and autolysosomes in H1975 and H1299 LUAD cells following BCAR1 knockout (KO) was conducted using transmission electron microscope. The expression of markers and cellular functions related to the UPR, autophagy, and VM formation were examined in LUAD cells tissues. Additionally, proteomic analysis of LUAD cells was performed via mass spectrometry, and the pertinent signaling pathways were analyzed using bioinformatics tools. RESULTS BCAR1-KO inhibited autophagy and UPR induced triggered starvation in LUAD cells. Cleaved-ATF6a-mediated UPR and subsequent autophagy, enhanced by BCAR1, were confirmed using the UPR stimulator and blocker. High BCAR1 expression, along with elevated UPR and autophagy, predicts poor prognosis in LUAD patients. BCAR1-KO reduced tube formation and VM markers expressions in LUAD cells. Additionally, BCAR1 expression positively correlated with VM formation in BALB/c-nu mice xenografts and LUAD patient tissues. CONCLUSION BCAR1 promotes LUAD metastasis by enhancing cancer cell survival in nutrient-poor environments through ATF6-mediated UPR activation and autophagy. As BCAR1 induces VM formation, metastatic lesions eventually colonize. Thus, BCAR1 is a promising anti-metastasis target.
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Affiliation(s)
- Chengyi Mao
- Department of Pathology, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Jingge Zhang
- Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Chuan Yang
- Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Longyong Mei
- Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Yonggeng Feng
- Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Fuqiang Dai
- Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Yi Huang
- Biomedical Analysis Center, Army Medical University, Chongqing 400038, China.
| | - Hualiang Xiao
- Department of Pathology, Daping Hospital, Army Medical University, Chongqing 400042, China.
| | - Bo Deng
- Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China.
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Hu Y, Yu Q, Li X, Wang J, Guo L, Huang L, Gao W. Nanoformula Design for Inducing Non-Apoptotic Cell Death Regulation: A Powerful Booster for Cancer Immunotherapy. Adv Healthc Mater 2025; 14:e2403493. [PMID: 39632361 DOI: 10.1002/adhm.202403493] [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: 11/03/2024] [Indexed: 12/07/2024]
Abstract
Cancer treatment has witnessed revolutionary advancements marked by the emergence of immunotherapy, specifically immune checkpoint blockade (ICB). However, the inherent low immunogenicity of tumor cells and the intricate immunosuppressive network within the tumor microenvironment (TME) pose significant challenges to the further development of immunotherapy. Nanotechnology has ushered in unprecedented opportunities and vast prospects for tumor immunotherapy. Nevertheless, traditional nano-formulations often rely on inducing apoptosis to kill cancer cells, which encounters the issue of immune silencing, hindering effective tumor immune activation. The non-apoptotic modes of regulated cell death (RCD), including pyroptosis, ferroptosis, autophagy, necroptosis, and cuproptosis, have gradually garnered attention. These non-apoptotic cell death pathways can induce effective immunogenic cell death (ICD), enhancing cancer immunotherapy. This review comprehensively explores advanced nano-formulation design strategies and their applications in enhancing cancer immunotherapy by promoting non-apoptotic RCD in recent years. It also discusses the potential advantages of these strategies in inducing tumor-specific non-apoptotic RCD. By deeply understanding the significance of non-apoptotic RCD in synergistic cancer immunotherapy, this article provides valuable insights for developing more advanced nano-delivery systems that can robustly induce highly immunogenic non-apoptotic modes, offering novel research and development avenues to address the clinical challenges encountered by immunotherapy represented by ICB.
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Affiliation(s)
- Yi Hu
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
| | - Qing Yu
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
| | - Xia Li
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
| | - Juan Wang
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
| | - Lanping Guo
- National Resource Center for Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Luqi Huang
- National Resource Center for Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Wenyuan Gao
- School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P.R. China
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Lee M, Son S, Lim HJ, Song H. The differential expression patterns of Atg9a and Atg9b in cells of the reproductive organs. Clin Exp Reprod Med 2024; 51:301-308. [PMID: 38757275 PMCID: PMC11617914 DOI: 10.5653/cerm.2023.06737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 02/26/2024] [Accepted: 03/12/2024] [Indexed: 05/18/2024] Open
Abstract
OBJECTIVE Autophagy is a major intracellular catabolic pathway governed by the sequential actions of proteins encoded by autophagy-related genes (Atg). ATG9, the only transmembrane protein involved in this process, regulates phospholipid translocation to autophagosomes during the early phases of autophagy. In mammals, two Atg9 isoforms have been reported: Atg9a and Atg9b. In this study, we examined whether the molecular and cellular characteristics of these two isoforms differed in mice. METHODS Whole uteri were collected on days 1, 4, and 8 of pregnancy and from ovariectomized mice injected with vehicle, progesterone, or 17β-estradiol. Cells from reproductive tissues, such as granulosa cells, uterine epithelial cells (UECs), uterine stromal cells (USCs), and oocytes were collected. Two human uterine cell lines were also used in this analysis. Reverse transcription-polymerase chain reaction tests, Western blotting, and immunofluorescence staining were performed. Serum starvation conditions were used to induce autophagy in primary cells. RESULTS Atg9a and Atg9b were expressed in multiple mouse tissues and reproductive cells. Neither Atg9A nor Atg9B significantly changed in response to steroid hormones. Immunofluorescence staining of the UECs and USCs showed that ATG9A was distributed in a punctate-like pattern, whereas ATG9B exhibited a pattern of elongated tubular shapes in the cytoplasm. In human cancer cell lines, ATG9B was undetectable, whereas ATG9A was found in all cell types examined. CONCLUSION The Atg9 isoforms exhibited distinct subcellular localizations in UECs and may play different roles in autophagy. Notably, human uterine cells exhibited reduced ATG9B expression, suggesting that this suppression may be due to epigenetic regulation.
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Affiliation(s)
- Minseo Lee
- Department of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Sujin Son
- Department of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Hyunjung J. Lim
- Department of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Haengseok Song
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
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Kubota Y, Kimura S. Current Understanding of the Role of Autophagy in the Treatment of Myeloid Leukemia. Int J Mol Sci 2024; 25:12219. [PMID: 39596291 PMCID: PMC11594995 DOI: 10.3390/ijms252212219] [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: 09/29/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
The most important issues in acute myeloid leukemia are preventing relapse and treating relapse. Although the remission rate has improved to approximately 80%, the 5-year survival rate is only around 30%. The main reasons for this are the high relapse rate and the limited treatment options. In chronic myeloid leukemia patients, when a deep molecular response is achieved for a certain period of time through tyrosine kinase inhibitor treatment, about half of them will reach treatment-free remission, but relapse is still a problem. Therefore, potential therapeutic targets for myeloid leukemias are eagerly awaited. Autophagy suppresses the development of cancer by maintaining cellular homeostasis; however, it also promotes cancer progression by helping cancer cells survive under various metabolic stresses. In addition, autophagy is promoted or suppressed in cancer cells by various genetic mutations. Therefore, the development of therapies that target autophagy is also being actively researched in the field of leukemia. In this review, studies of the role of autophagy in hematopoiesis, leukemogenesis, and myeloid leukemias are presented, and the impact of autophagy regulation on leukemia treatment and the clinical trials of autophagy-related drugs to date is discussed.
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MESH Headings
- Humans
- Autophagy
- Animals
- Leukemia, Myeloid/pathology
- Leukemia, Myeloid/genetics
- Leukemia, Myeloid/therapy
- Leukemia, Myeloid/metabolism
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/drug therapy
- Antineoplastic Agents/therapeutic use
- Antineoplastic Agents/pharmacology
- Hematopoiesis
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Affiliation(s)
- Yasushi Kubota
- Department of Clinical Laboratory Medicine, Saga-Ken Medical Centre Koseikan, Saga 840-8571, Japan
| | - Shinya Kimura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan;
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Zhao J, Xu Z, Xie J, Liang T, Wang R, Chen W, Mi C, Tian P, Guo J, Zhang H. The novel lnc-HZ12 suppresses autophagy degradation of BBC3 by preventing its interactions with HSPA8 to induce trophoblast cell apoptosis. Autophagy 2024; 20:2255-2274. [PMID: 38836496 PMCID: PMC11423690 DOI: 10.1080/15548627.2024.2362122] [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: 07/11/2023] [Revised: 05/19/2024] [Accepted: 05/28/2024] [Indexed: 06/06/2024] Open
Abstract
Abnormal expression of long non-coding RNAs (lncRNAs) is associated with the dysfunctions of human trophoblast cells and the occurrence of miscarriage (abnormal early embryo loss). BBC3/PUMA (BCL2 binding component 3) plays significant roles in regulation of cell apoptosis. However, whether specific lncRNAs might regulate BBC3 in trophoblast cells and further induce apoptosis and miscarriage remains completely unclear. Through screening, we identified a novel lnc-HZ12, which was significantly highly expressed in villous tissues of recurrent miscarriage (RM) patients relative to their healthy control (HC) group. Lnc-HZ12 suppressed chaperone-mediated autophagy (CMA) degradation of BBC3, promoted trophoblast cell apoptosis, and was associated with miscarriage. In mechanism, lnc-HZ12 downregulated the expression levels of chaperone molecules HSPA8 and LAMP2A in trophoblast cells. Meanwhile, lnc-HZ12 (mainly lnc-HZ12-SO2 region in F2 fragment) and HSPA8 competitively bound with the 169RVLYNL174 patch on BBC3, which prevented BBC3 from interactions with HSPA8 and impaired the formation of BBC3-HSPA8-LAMP2A complex for CMA degradation of BBC3. Thus, lnc-HZ12 upregulated the BBC3-CASP9-CASP3 pathway and induced trophoblast cell apoptosis. In villous tissues, lnc-HZ12 was highly expressed, CMA degradation of BBC3 was suppressed, and the apoptosis levels were higher in RM vs HC villous tissues, all of which were associated with miscarriage. Interestingly, knockdown of murine Bbc3 could efficiently suppress placental apoptosis and alleviate miscarriage in a mouse miscarriage model. Taken together, our results indicated that lnc-HZ12 and BBC3 played important roles in trophoblast cell apoptosis and miscarriage and might act as attractive targets for miscarriage treatment.Abbreviation: 7-AAD: 7-aminoactinomycin D; BaP: benzopyrene; BBC3/PUMA: BCL2 binding component 3; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; DMSO: dimethyl sulfoxide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HC: healthy control; HSPA8: heat shock protein family A (Hsp70) member 8; IP: immunoprecipitation; LAMP2A: lysosomal associated membrane protein 2; LncRNA: long non-coding RNA; mRNA: messenger RNA; MT: mutant-type; NC: negative control; NSO: nonspecific oligonucleotide; PARP1: poly(ADP-ribose) polymerase 1; RIP: RNA immunoprecipitation; RM: recurrent miscarriage; TBP: TATA-box binding protein; WT: wild-type.
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Affiliation(s)
- Jingsong Zhao
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China
| | - Zhongyan Xu
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China
| | - Jiayu Xie
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Tingting Liang
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Rong Wang
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Weina Chen
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Chenyang Mi
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Peng Tian
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Jiarong Guo
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Huidong Zhang
- Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
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Gupta KB, Gao J, Li X, Thangaraju M, Panda SS, Lokeshwar BL. Cytotoxic Autophagy: A Novel Treatment Paradigm against Breast Cancer Using Oleanolic Acid and Ursolic Acid. Cancers (Basel) 2024; 16:3367. [PMID: 39409987 PMCID: PMC11476055 DOI: 10.3390/cancers16193367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/26/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND Oleanolic acid (OA) and Ursolic acid (UA) are bioactive triterpenoids. Reported activities vary with the dose used for testing their activities in vitro. Studies using doses of ≥20 µM showed apoptosis activities in cancer cells. However, reported drug levels in circulation achieved by oral administration of UA and OA are ≤2 µM, thus limiting their use for treatment or delivering a combination treatment. MATERIALS AND METHODS The present report demonstrates the efficacy of OA, UA, and OA + UA on tumor cell-specific cytotoxicity at low doses (5 µM to 10 µM) in breast cancer (BrCa) cell lines MCF7 and MDA-MB231. RESULTS The data show that both OA and UA killed BrCa cells at low doses, but were significantly less toxic to MCF-12A, a non-tumorigenic cell line. Moreover, OA + UA at ≤10 µM was lethal to BrCa cells. Mechanistic studies unraveled the significant absence of apoptosis, but their cytotoxicity was due to the induction of excessive autophagy at a OA + UA dose of 5 µM each. A link to drug-induced cytotoxic autophagy was established by demonstrating a lack of their cytotoxicity by silencing the autophagy-targeting genes (ATGs), which prevented OA-, UA-, or OA + UA-induced cell death. Further, UA or OA + UA treatment of BrCa cells caused an inhibition of PI3 kinase-mediated phosphorylation of Akt/mTOR, the key pathways that regulate cancer cell survival, metabolism, and proliferation. DISCUSSION Combinations of a PI3K inhibitor (LY294002) with OA, UA, or OA + UA synergistically inhibited BrCa cell survival. Therefore, the dominance of cytotoxic autophagy by inhibiting PI3K-mediated autophagy may be the primary mechanism of PTT-induced anticancer activity in BrCa cells. CONCLUSION These results suggest it would be worthwhile testing combined OA and UA in clinical settings.
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Affiliation(s)
- Kunj Bihari Gupta
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; (K.B.G.); (J.G.); (X.L.)
| | - Jie Gao
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; (K.B.G.); (J.G.); (X.L.)
- Department of Clinical and Diagnostic Science, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Xin Li
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; (K.B.G.); (J.G.); (X.L.)
- The Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (M.T.); (S.S.P.)
| | - Siva S. Panda
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (M.T.); (S.S.P.)
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Augusta University, Augusta, GA 30912, USA
| | - Bal L. Lokeshwar
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; (K.B.G.); (J.G.); (X.L.)
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11
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He L, Tian Y, Liu Q, Bao J, Ding RB. Antidepressant Sertraline Synergistically Enhances Paclitaxel Efficacy by Inducing Autophagy in Colorectal Cancer Cells. Molecules 2024; 29:3733. [PMID: 39202813 PMCID: PMC11357241 DOI: 10.3390/molecules29163733] [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: 05/13/2024] [Revised: 07/19/2024] [Accepted: 07/24/2024] [Indexed: 09/03/2024] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. It is important to discover new therapeutic regimens for treating CRC. Depression is known to be an important complication of cancer diseases. Repurposing antidepressants into anticancer drugs and exploring the combinational efficacy of antidepressants and chemotherapy are potentially good options for developing CRC treatment regimens. In this study, sertraline, an antidepressant drug, and paclitaxel, an anticancer drug, were chosen to study their antitumor effects in the treatment of colorectal cancer, alone or in combination, and to explore their underlying mechanisms. The data showed that sertraline exerted a dose-dependent cytotoxic effect on MC38 and CT26 colorectal cancer cell lines with IC50 values of 10.53 μM and 7.47 μM, respectively. Furthermore, sertraline synergistically sensitized chemotherapeutic agent paclitaxel efficacy in CRC cells with combination index (CI) values at various concentrations consistently lower than 1. Sertraline remarkably augmented paclitaxel-induced autophagy by increasing autophagosome formation indicated by elevated LC3-II/I ratio and promoting autophagic flux by degrading autophagy cargo receptor SQSTM1/p62, which may explain the synergistically cytotoxic effect of sertraline and paclitaxel combination therapy on CRC cells. This study provides important evidence to support repurposing sertraline as an anticancer agent and suggests a novel combinational regimen for effectively treating CRC as well as in the simultaneous treatment of CRC and depression.
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Affiliation(s)
- Leping He
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou 570228, China; (L.H.); (Y.T.); (Q.L.); (J.B.)
| | - Yuxi Tian
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou 570228, China; (L.H.); (Y.T.); (Q.L.); (J.B.)
| | - Qingqing Liu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou 570228, China; (L.H.); (Y.T.); (Q.L.); (J.B.)
| | - Jiaolin Bao
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou 570228, China; (L.H.); (Y.T.); (Q.L.); (J.B.)
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Ren-Bo Ding
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou 570228, China; (L.H.); (Y.T.); (Q.L.); (J.B.)
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
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12
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Li Y, Zhang Y, Wang M, Su J, Dong X, Yang Y, Wang H, Li Q. The mammalian actin elongation factor ENAH/MENA contributes to autophagosome formation via its actin regulatory function. Autophagy 2024; 20:1798-1814. [PMID: 38705725 PMCID: PMC11262208 DOI: 10.1080/15548627.2024.2347105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 04/07/2024] [Accepted: 04/19/2024] [Indexed: 05/07/2024] Open
Abstract
Macroautophagy/autophagy is a catabolic process crucial for degrading cytosolic components and damaged organelles to maintain cellular homeostasis, enabling cells to survive in extreme extracellular environments. ENAH/MENA, a member of the Ena/VASP protein family, functions as a highly efficient actin elongation factor. In this study, our objective was to explore the role of ENAH in the autophagy process. Initially, we demonstrated that depleting ENAH in cancer cells inhibits autophagosome formation. Subsequently, we observed ENAH's colocalization with MAP1LC3/LC3 during tumor cell starvation, dependent on actin cytoskeleton polymerization and the interaction between ENAH and BECN1 (beclin 1). Additionally, mammalian ATG9A formed a ring-like structure around ENAH-LC3 puncta during starvation, relying on actin cytoskeleton polymerization. Furthermore, ENAH's EVH1 and EVH2 domains were found to be indispensable for its colocalization with LC3 and BECN1, while the PRD domain played a crucial role in the formation of the ATG9A ring. Finally, our study revealed ENAH-led actin comet tails in autophagosome trafficking. In conclusion, our findings provide initial insights into the regulatory role of the mammalian actin elongation factor ENAH in autophagy.Abbreviations: 3-MA 3-methyladenine; ABPs actin-binding proteins; ATG autophagy related; ATG9A autophagy related 9A; Baf A1 bafilomycin A1; CM complete medium; CytERM endoplasmic reticulum signal-anchor membrane protein; Cyto D cytochalasin D; EBSS Earl's balanced salt solution; ENAH/MENA ENAH actin regulator; EVH1 Ena/VASP homology 1 domain; EVH2 Ena/VASP homology 2 domain; GAPDH glyceraldehyde-3-phosphate dehydrogenase; Lat B latrunculin B; LC3-I unlipidated form of LC3; LC3-II phosphatidylethanolamine-conjugated form of LC3; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; mEGFP monomeric enhanced green fluorescent protein; mTagBFP2 monomeric Tag blue fluorescent protein 2; OSER organized smooth endoplasmic reticulum; PRD proline-rich domain; PtdIns3K class III phosphatidylinositol 3-kinase; WM wortmannin.
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Affiliation(s)
- Yueheng Li
- Department of Pathology, School of Basic Medical Science, Fudan University, Shanghai, China
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Yafei Zhang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui province, China
| | - Menghui Wang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Junhui Su
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Xinjue Dong
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Yuqi Yang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Hongshan Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - QingQuan Li
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui province, China
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13
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Li R, Geng H, Tan X, Wang J, Deng L. Stanniocalcin 2 Regulates Autophagy and Ferroptosis in Mammary Epithelial Cells of Dairy Cows Through the Mechanistic Target of Rapamycin Complex 1 Pathway. J Nutr 2024; 154:1790-1802. [PMID: 38636707 DOI: 10.1016/j.tjnut.2024.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 04/05/2024] [Accepted: 04/15/2024] [Indexed: 04/20/2024] Open
Abstract
BACKGROUND Stanniocalcin 2 (STC2), a glycoprotein hormone, is extensively expressed in various organs and tissues, particularly in the mammary gland. STC2 plays a crucial role in enabling cells to adapt to stress conditions and avert apoptosis. The efficiency of milk production is closely linked to both the quantity and quality of mammary cells. Yet, there remains a dearth of research on the impact of STC2 on mammary cells' activity in dairy cows. OBJECTIVES The objective of this study was to investigate the effects of STC2 on the viability of mammary epithelial cells in dairy cows and to elucidate the underlying mechanisms. METHODS First, the Gene Expression Profiling and Interactive Analysis database was employed to perform survival analysis on STC2 expression in relation to prognosis using The Cancer Genome Atlas and GETx data. Subsequently, the basic physical and chemical properties, gene expression, and potential signaling pathways involved in the growth of dairy cow mammary epithelial cells were determined using STC2 knockdown. RESULTS STC2 knockdown significantly suppressed autophagy in mammary epithelial cells of dairy cows. Moreover, STC2 knockdown upregulated glutathione peroxidase 4 protein expression, elicited an elevation in lipid ROS concentrations, and inhibited the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, consequently repressing downstream genes involved in lipid synthesis regulated by mTORC1 and ultimately inducing ferroptosis. CONCLUSIONS The findings of our study suggest that STC2 suppresses autophagy and ferroptosis through the activation of mTORC1. Mechanically, STC2 exerts an inhibitory effect on ferroptosis by activating antioxidative stress-related proteins, such as glutathione peroxidase 4, to suppress lipid ROS production and stimulating the mTORC1 signaling pathway to enhance the expression of genes associated with lipid synthesis.
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Affiliation(s)
- RongNuo Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - HuiJun Geng
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Xiao Tan
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - JiangXin Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Lu Deng
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China; Shenzhen Research Institute, Northwest A&F University, Shenzhen, Guangdong, China.
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14
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Pandori WJ, Matsuno SY, Shin JH, Kim SC, Kao TH, Mallya S, Batarseh SN, Lodoen MB. Role for Caspase-8 in the Release of IL-1β and Active Caspase-1 from Viable Human Monocytes during Toxoplasma gondii Infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1161-1171. [PMID: 38372637 PMCID: PMC11410338 DOI: 10.4049/jimmunol.2200513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 01/16/2024] [Indexed: 02/20/2024]
Abstract
Monocytes are actively recruited to sites of infection and produce the potent proinflammatory cytokine IL-1β. We previously showed that IL-1β release during Toxoplasma gondii infection of primary human monocytes requires the NLRP3 inflammasome and caspase-1 but is independent of gasdermin D and pyroptosis. To investigate mechanisms of IL-1β release, we generated caspase-1, -4, -5, or -8 knockout (KO) THP-1 monocytic cells. Genetic ablation of caspase-1 or -8, but not caspase-4 or -5, decreased IL-1β release during T. gondii infection without affecting cell death. In contrast, TNF-α and IL-6 secretion were unperturbed in caspase-8 KO cells during T. gondii infection. Dual pharmacological inhibition of caspase-8 and RIPK1 in primary monocytes also decreased IL-1β release without affecting cell viability or parasite infection. Caspase-8 was also required for the release of active caspase-1 from T. gondii-infected cells and for IL-1β release during infection with the related apicomplexan parasite Neospora caninum. Surprisingly, caspase-8 deficiency did not impair synthesis or cleavage of pro-IL-1β, but resulted in the retention of mature IL-1β within cells. Generation of gasdermin E KO and ATG7 KO THP-1 cells revealed that the release of IL-1β was not dependent on gasdermin E or ATG7. Collectively, our data indicate that during T. gondii Infection of human monocytes, caspase-8 functions in a novel gasdermin-independent mechanism controlling IL-1β release from viable cells. This study expands on the molecular pathways that promote IL-1β in human immune cells and provides evidence of a role for caspase-8 in the mechanism of IL-1β release during infection.
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Affiliation(s)
- William J. Pandori
- Department of Molecular Biology & Biochemistry and the Institute for Immunology, University of California, Irvine, California, 92617, USA
| | - Stephanie Y. Matsuno
- Department of Molecular Biology & Biochemistry and the Institute for Immunology, University of California, Irvine, California, 92617, USA
| | - Ji-Hun Shin
- Department of Molecular Biology & Biochemistry and the Institute for Immunology, University of California, Irvine, California, 92617, USA
| | - Samuel C. Kim
- Department of Molecular Biology & Biochemistry and the Institute for Immunology, University of California, Irvine, California, 92617, USA
| | - Tiffany H. Kao
- Department of Molecular Biology & Biochemistry and the Institute for Immunology, University of California, Irvine, California, 92617, USA
| | - Sharmila Mallya
- Department of Molecular Biology & Biochemistry and the Institute for Immunology, University of California, Irvine, California, 92617, USA
| | - Sarah N. Batarseh
- Department of Molecular Biology & Biochemistry and the Institute for Immunology, University of California, Irvine, California, 92617, USA
| | - Melissa B. Lodoen
- Department of Molecular Biology & Biochemistry and the Institute for Immunology, University of California, Irvine, California, 92617, USA
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15
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Lee S, Kim YH, Min J. The potential of Rhodobacter sphaeroides extract as an alternative supplement for cell culture systems. Microbiol Spectr 2024; 12:e0245623. [PMID: 38319116 PMCID: PMC10913442 DOI: 10.1128/spectrum.02456-23] [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: 06/13/2023] [Accepted: 01/12/2024] [Indexed: 02/07/2024] Open
Abstract
It is essential to identify suitable supplements that enhance cell growth, viability, and functional development in cell culture systems. The use of fetal bovine serum (FBS) has been common, but it has limitations, such as batch-to-batch variability, ethical concerns, and risks of environmental contamination. In this study, we explore the potential of Rhodobacter sphaeroides extract, derived from a probiotic photosynthetic bacterium, as an alternative supplement. Our results demonstrate that the extract from R. sphaeroides significantly improves various aspects of cell behavior compared to serum-free conditions. It enhances cell growth and viability to a greater extent than FBS supplementation. Additionally, the extract alleviates oxidative stress by reducing intracellular levels of reactive oxygen species and stimulates lysosomal activity, contributing to cellular processes. The presence of abundant amino acids, glycine and arginine, in the extract may play a role in promoting cell growth. These findings emphasize the potential of R. sphaeroides extract as a valuable supplement for cell culture, offering advantages over the use of FBS.IMPORTANCEThe choice of supplements for cell culture is crucial in biomedical research, but the widely used fetal bovine serum (FBS) has limitations in terms of variability, ethics, and environmental risks. This study explores the potential of an extract from Rhodobacter sphaeroides, a probiotic bacterium, as an alternative supplement. The findings reveal that the R. sphaeroides extract surpasses FBS in enhancing cell growth, viability, and functionality. It also mitigates oxidative stress and stimulates lysosomal activity, critical for cellular health. The extract's abundance of glycine and arginine, amino acids with known growth-promoting effects, further highlights its potential. By providing a viable substitute for FBS, the R. sphaeroides extract addresses the need for consistent, ethical, and environmentally friendly cell culture supplements. This research paves the way for sustainable and reliable cell culture systems, revolutionizing biomedical research and applications in drug development and regenerative medicine.
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Affiliation(s)
- Subin Lee
- Department of Bioprocess Engineering, Jeonbuk National University, Jeonju, Jeonbuk, South Korea
| | - Yang-Hoon Kim
- School of Biological Sciences, Chungbuk National University, Cheongju, South Korea
| | - Jiho Min
- Department of Bioprocess Engineering, Jeonbuk National University, Jeonju, Jeonbuk, South Korea
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16
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Kumar S, Shenoy S, Swamy RS, Ravichandiran V, Kumar N. Fluoride-Induced Mitochondrial Dysfunction and Approaches for Its Intervention. Biol Trace Elem Res 2024; 202:835-849. [PMID: 37300595 DOI: 10.1007/s12011-023-03720-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 05/28/2023] [Indexed: 06/12/2023]
Abstract
Fluoride is present everywhere in nature. The primary way that individuals are exposed to fluoride is by drinking water. It's interesting to note that while low fluoride levels are good for bone and tooth growth, prolonged fluoride exposure is bad for human health. Additionally, preclinical studies link oxidative stress, inflammation, and programmed cell death to fluoride toxicity. Moreover, mitochondria play a crucial role in the production of reactive oxygen species (ROS). On the other hand, little is known about fluoride's impact on mitophagy, biogenesis, and mitochondrial dynamics. These actions control the growth, composition, and organisation of mitochondria, and the purification of mitochondrial DNA helps to inhibit the production of reactive oxygen species and the release of cytochrome c, which enables cells to survive the effects of fluoride poisoning. In this review, we discuss the different pathways involved in mitochondrial toxicity and dysfunction induced by fluoride. For therapeutic approaches, we discussed different phytochemical and pharmacological agents which reduce the toxicity of fluoride via maintained by imbalanced cellular processes, mitochondrial dynamics, and scavenging the ROS.
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Affiliation(s)
- Sachindra Kumar
- National Institute of Pharmaceutical Education and Research, Hajipur, Industrial Area Hajipur, Vaishali, 844102, India
| | - Smita Shenoy
- Department of Pharmacology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
| | - Ravindra Shantakumar Swamy
- Division of Anatomy, Department of Basic Medical Sciences (DBMS), Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
| | - V Ravichandiran
- National Institute of Pharmaceutical Education and Research, Hajipur, Industrial Area Hajipur, Vaishali, 844102, India
| | - Nitesh Kumar
- National Institute of Pharmaceutical Education and Research, Hajipur, Industrial Area Hajipur, Vaishali, 844102, India.
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17
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Xu Y, Shao B, Zhang Y. The significance of targeting lysosomes in cancer immunotherapy. Front Immunol 2024; 15:1308070. [PMID: 38370407 PMCID: PMC10869645 DOI: 10.3389/fimmu.2024.1308070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 01/22/2024] [Indexed: 02/20/2024] Open
Abstract
Lysosomes are intracellular digestive organelles that participate in various physiological and pathological processes, including the regulation of immune checkpoint molecules, immune cell function in the tumor microenvironment, antigen presentation, metabolism, and autophagy. Abnormalities or dysfunction of lysosomes are associated with the occurrence, development, and drug resistance of tumors. Lysosomes play a crucial role and have potential applications in tumor immunotherapy. Targeting lysosomes or harnessing their properties is an effective strategy for tumor immunotherapy. However, the mechanisms and approaches related to lysosomes in tumor immunotherapy are not fully understood at present, and further basic and clinical research is needed to provide better treatment options for cancer patients. This review focuses on the research progress related to lysosomes and tumor immunotherapy in these.
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Affiliation(s)
- Yanxin Xu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, China
| | - Bo Shao
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, China
| | - Yafeng Zhang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, China
- Institute for Hospital Management of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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18
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Liu Y, Wang T, Ma W, Jia Z, Wang Q, Zhang M, Luo Y, Sun H. Metabolic reprogramming in the tumor microenvironment: unleashing T cell stemness for enhanced cancer immunotherapy. Front Pharmacol 2023; 14:1327717. [PMID: 38169800 PMCID: PMC10758489 DOI: 10.3389/fphar.2023.1327717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 12/01/2023] [Indexed: 01/05/2024] Open
Abstract
T cells play a pivotal role in the immune system by distinguishing between various harmful pathogens and cancerous cells within the human body and initiating an immune response. Within the tumor microenvironment (TME), immune effector T cells encounter both immunosuppressive cells and factors that hinder their functionality. Additionally, they endure robust and persistent antigenic stimulation, often leading to exhaustion and apoptosis. However, the stemness of T cells, characterized by their ability to survive and self-renew over extended periods, represents a primary target in immune checkpoint therapies such as anti-PD-1 therapy. T cell stemness encompasses specific memory T cell subsets and progenitor-exhausted T cells with stem cell-like properties. Therefore, understanding the impact of the TME on T cell stemness, including factors like K+, lactate, and H+, holds significant importance and can facilitate the mitigation of terminal T-cell depletion, the identification of potential resilient biomarkers or therapeutic targets resistant to immune checkpoint therapies, and ultimately lead to sustained anti-tumor effects. Thus, it offers a novel perspective for advancing tumor immunotherapy.
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Affiliation(s)
- Youhan Liu
- College of Sport and Health, Shandong Sport University, Jinan, China
| | - Tao Wang
- Department of Pediatric Surgery, Zibo Central Hospital, Zibo, China
| | - Wen Ma
- College of Sport and Health, Shandong Sport University, Jinan, China
| | - Zixuan Jia
- College of Sport and Health, Shandong Sport University, Jinan, China
| | - Qinglu Wang
- College of Sport and Health, Shandong Sport University, Jinan, China
| | - Maoling Zhang
- College of Sport and Health, Shandong Sport University, Jinan, China
| | - Ying Luo
- Department of Clinical Laboratory, Zibo Central Hospital, Zibo, China
| | - Hongmei Sun
- College of Sport and Health, Shandong Sport University, Jinan, China
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19
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Lin L, Zhao Y, Zheng Q, Zhang J, Li H, Wu W. Epigenetic targeting of autophagy for cancer: DNA and RNA methylation. Front Oncol 2023; 13:1290330. [PMID: 38148841 PMCID: PMC10749975 DOI: 10.3389/fonc.2023.1290330] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/28/2023] [Indexed: 12/28/2023] Open
Abstract
Autophagy, a crucial cellular mechanism responsible for degradation and recycling of intracellular components, is modulated by an intricate network of molecular signals. Its paradoxical involvement in oncogenesis, acting as both a tumor suppressor and promoter, has been underscored in recent studies. Central to this regulatory network are the epigenetic modifications of DNA and RNA methylation, notably the presence of N6-methyldeoxyadenosine (6mA) in genomic DNA and N6-methyladenosine (m6A) in eukaryotic mRNA. The 6mA modification in genomic DNA adds an extra dimension of epigenetic regulation, potentially impacting the transcriptional dynamics of genes linked to autophagy and, especially, cancer. Conversely, m6A modification, governed by methyltransferases and demethylases, influences mRNA stability, processing, and translation, affecting genes central to autophagic pathways. As we delve deeper into the complexities of autophagy regulation, the importance of these methylation modifications grows more evident. The interplay of 6mA, m6A, and autophagy points to a layered regulatory mechanism, illuminating cellular reactions to a range of conditions. This review delves into the nexus between DNA 6mA and RNA m6A methylation and their influence on autophagy in cancer contexts. By closely examining these epigenetic markers, we underscore their promise as therapeutic avenues, suggesting novel approaches for cancer intervention through autophagy modulation.
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Affiliation(s)
- Luobin Lin
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Yuntao Zhao
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Qinzhou Zheng
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Jiayang Zhang
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Huaqin Li
- School of Health Sciences, Guangzhou Xinhua University, Guangzhou, Guangdong, China
| | - Wenmei Wu
- Guangdong Province Key Laboratory of Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
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20
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Pino-Jiménez B, Giannios P, Casanova J. Polyploidy-associated autophagy promotes larval tracheal histolysis at Drosophila metamorphosis. Autophagy 2023; 19:2972-2981. [PMID: 37424089 PMCID: PMC10549192 DOI: 10.1080/15548627.2023.2231828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 06/14/2023] [Accepted: 06/27/2023] [Indexed: 07/11/2023] Open
Abstract
Polyploidy is an extended phenomenon in biology. However, its physiological significance and whether it defines specific cell behaviors is not well understood. Here we study its connection to macroautophagy/autophagy, using the larval respiratory system of Drosophila as a model. This system comprises cells with the same function yet with notably different ploidy status, namely diploid progenitors and their polyploid larval counterparts, the latter destined to die during metamorphosis. We identified an association between polyploidy and autophagy and found that higher endoreplication status correlates with elevated autophagy. Finally, we report that tissue histolysis in the trachea during Drosophila metamorphosis is mediated by autophagy, which triggers the apoptosis of polyploid cells.Abbreviations: APF: after pupa formation; Atg: autophagy related; btl: breathless; CycE: Cyclin E; DT: dorsal trunk; fzr: fizzy-related; L3: larval stage 3; PBS: phosphate-buffered saline; RI: RNAi; Tr: tracheal metamere; yki: yorkie.
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Affiliation(s)
- Beatriz Pino-Jiménez
- Department of Cell and Tissues, Institut de Biologia Molecular de Barcelona (CSIC), Barcelona, Catalonia, Spain
- Institut de Recerca Biomèdica de Barcelona, (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Catalonia, Spain
| | - Panagiotis Giannios
- Department of Cell and Tissues, Institut de Biologia Molecular de Barcelona (CSIC), Barcelona, Catalonia, Spain
- Institut de Recerca Biomèdica de Barcelona, (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Catalonia, Spain
| | - Jordi Casanova
- Department of Cell and Tissues, Institut de Biologia Molecular de Barcelona (CSIC), Barcelona, Catalonia, Spain
- Institut de Recerca Biomèdica de Barcelona, (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Catalonia, Spain
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Tamargo-Gómez I, Martínez-García GG, Suárez MF, Mayoral P, Bretones G, Astudillo A, Prieto-Lloret J, Sveen C, Fueyo A, Engedal N, López-Otín C, Mariño G. Analysis of ATG4C function in vivo. Autophagy 2023; 19:2912-2933. [PMID: 37459465 PMCID: PMC10549197 DOI: 10.1080/15548627.2023.2234799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 06/23/2023] [Accepted: 07/05/2023] [Indexed: 08/17/2023] Open
Abstract
ABBREVIATIONS ATG4 (autophagy related 4 cysteine peptidase); ATG4A (autophagy related 4A cysteine peptidase); ATG4B (autophagy related 4B cysteine peptidase); ATG4C (autophagy related 4C cysteine peptidase); ATG4D (autophagy related 4D cysteine peptidase); Atg8 (autophagy related 8); GABARAP (GABA type A receptor-associated protein); GABARAPL1(GABA type A receptor-associated protein like 1); GABARAPL2 (GABA type A receptor-associated protein like 2); MAP1LC3A/LC3A (microtubule associated protein 1 light chain 3 alpha); MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta); mATG8 (mammalian Atg8); PE (phosphatidylethanolamine); PS (phosphatydylserine); SQSTM1/p62 (sequestosome 1).
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Affiliation(s)
- Isaac Tamargo-Gómez
- Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
- Instituto Universitario de Oncología (IUOPA), Oviedo, Spain
- Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Oviedo, Spain
| | - Gemma G. Martínez-García
- Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
- Instituto Universitario de Oncología (IUOPA), Oviedo, Spain
- Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Oviedo, Spain
| | - María F. Suárez
- Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Oviedo, Spain
| | - Pablo Mayoral
- Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Spain
| | - Gabriel Bretones
- Instituto Universitario de Oncología (IUOPA), Oviedo, Spain
- Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Spain
| | - Aurora Astudillo
- Instituto Universitario de Oncología (IUOPA), Oviedo, Spain
- Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Oviedo, Spain
- Biobanco Del Principado de Asturias (BBPA_ISPA_IUOPA), Registro Nacional de Biobancos PT20/161, Oviedo, Spain
| | - Jesús Prieto-Lloret
- Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid. Instituto de Biología y Genética Molecular-CSIC, Valladolid, Spain
| | - Christina Sveen
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Norway
| | - Antonio Fueyo
- Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
- Instituto Universitario de Oncología (IUOPA), Oviedo, Spain
- Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Oviedo, Spain
| | - Nikolai Engedal
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Norway
| | - Carlos López-Otín
- Instituto Universitario de Oncología (IUOPA), Oviedo, Spain
- Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Oviedo, Spain
- Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Spain
| | - Guillermo Mariño
- Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
- Instituto Universitario de Oncología (IUOPA), Oviedo, Spain
- Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Oviedo, Spain
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22
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Lê HG, Kang JM, Võ TC, Na BK. Kaempferol induces programmed cell death in Naegleria fowleri. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 119:154994. [PMID: 37597363 DOI: 10.1016/j.phymed.2023.154994] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/21/2023] [Accepted: 07/22/2023] [Indexed: 08/21/2023]
Abstract
BACKGROUND Naegleria fowleri is a brain-eating amoeba causing a fatal brain infection called primary amoebic meningoencephalitis (PAM). Despite its high mortality over 95%, effective therapeutic drug for PAM has not been developed yet. Therefore, development of an effective and safe therapeutic drug for PAM is urgently needed. In this study, we investigated anti-amoebic effect of kaempferol (KPF) against N. fowleri and its underlying anti-amoebic molecular mechanisms. METHODS Anti-amoebic activity of KPF against N. fowleri trophozoites, as well as cytotoxicity of KPF in C6 glial cells and CHO-K1 cells were investigated. The programmed cell death mechanisms in KPF-treated N. fowleri were also analyzed by apoptosis-necrosis assay, mitochondrial dysfunction assay, TUNEL assay, RT-qPCR, and CYTO-ID assay. RESULTS KPF showed anti-amoebic activity against N. fowleri trophozoites with an IC50 of 29.28 ± 0.63 μM. However, it showed no significant cytotoxicity to mammalian cells. KPF induced significant morphological alterations of the amoebae, resulting in death. Signals associated with apoptosis were detected in the amoebae upon treatment with KPF. KPF induced an increase of intracellular reactive oxygen species level, loss of mitochondrial membrane potential, increases of expression levels of genes associated with mitochondria dysfunction, and reduction of ATP levels in the amoebae. Autophagic vacuole accumulations with increased expression levels of autophagy-related genes were also detected in KPF-treated amoebae. CONCLUSION KPF induces programmed cell death in N. fowleri trophozoites via apoptosis-like pathway and autophagy pathway. KPF could be used as a candidate of anti-amoebic drug or supplement compound in the process of developing or optimizing therapeutic drug for PAM.
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Affiliation(s)
- Hương Giang Lê
- Department of Parasitology and Tropical Medicine, Institute of Health Science, Gyeongsang National University College of Medicine, Jinju 52727, Korea; Department of Convergence Medical Science, Gyeongsang National University, Jinju 52727, Korea
| | - Jung-Mi Kang
- Department of Parasitology and Tropical Medicine, Institute of Health Science, Gyeongsang National University College of Medicine, Jinju 52727, Korea; Department of Convergence Medical Science, Gyeongsang National University, Jinju 52727, Korea
| | - Tuấn Cường Võ
- Department of Parasitology and Tropical Medicine, Institute of Health Science, Gyeongsang National University College of Medicine, Jinju 52727, Korea; Department of Convergence Medical Science, Gyeongsang National University, Jinju 52727, Korea
| | - Byoung-Kuk Na
- Department of Parasitology and Tropical Medicine, Institute of Health Science, Gyeongsang National University College of Medicine, Jinju 52727, Korea; Department of Convergence Medical Science, Gyeongsang National University, Jinju 52727, Korea.
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23
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Zhou C, Zou Y, Hu Z, Yang MJ, Shi P, Li YR, Guo YJ, Zhang T, Song H. ROS-induced moderate autophagy of haemocytes confers resistance of Mercenaria mercenaria to air exposure stress. FISH & SHELLFISH IMMUNOLOGY 2023; 141:109084. [PMID: 37722439 DOI: 10.1016/j.fsi.2023.109084] [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: 07/29/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 09/20/2023]
Abstract
Air exposure (AE) is a significant environmental stressor that can lead to desiccation, hypoxia, starvation, and disruption of cellular homeostasis in marine bivalves. Autophagy is a highly conserved catabolic pathway that facilitates the degradation of damaged macromolecules and organelles, thereby supporting cellular stress responses. To date, autophagy-mediated resistance mechanisms to AE stress remain largely elusive in bivalves. In this study, we performed a multi-tool approach to investigate the autophagy-related physiological regulation in hard clams (Mercenaria mercenaria) under different duration of AE (T = 0, 1, 5, 10, 20, 30 days). We observed that autophagy of haemocytes was significantly activated on day 5. However, autophagy activity began to significantly decline from day 10 to day 30. Autophagy was significantly inhibited after antioxidant treatment, indicating that reactive oxygen species (ROS) was an endogenous inducer of autophagy. A significant decline in the survival rate of hard clams was observed after injection of ammonium chloride or carbamazepine during AE stress, suggesting that moderate autophagy was conducive for clam survival under AE stress. We also observed DNA breaks and high levels of apoptosis in haemocytes on day 10. Activation of apoptosis lagged behind autophagy, and the relationship between autophagy and apoptosis might shift from antagonism to synergy with the duration of stress. This study provides novel insights into the stress resistance mechanisms in marine bivalves.
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Affiliation(s)
- Cong Zhou
- CAS Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory for Marine Ecology and Environmental Science, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071, China; CAS Engineering Laboratory for Marine Ranching, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Shandong Province Key Laboratory of Experimental Marine Biology, Qingdao, 266071, China
| | - Yan Zou
- Marine Science Research Institute of Shandong Province, Qingdao, 266100, China
| | - Zhi Hu
- CAS Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory for Marine Ecology and Environmental Science, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071, China; CAS Engineering Laboratory for Marine Ranching, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Shandong Province Key Laboratory of Experimental Marine Biology, Qingdao, 266071, China
| | - Mei-Jie Yang
- CAS Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory for Marine Ecology and Environmental Science, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071, China; CAS Engineering Laboratory for Marine Ranching, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Shandong Province Key Laboratory of Experimental Marine Biology, Qingdao, 266071, China
| | - Pu Shi
- CAS Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory for Marine Ecology and Environmental Science, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071, China; CAS Engineering Laboratory for Marine Ranching, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Shandong Province Key Laboratory of Experimental Marine Biology, Qingdao, 266071, China
| | - Yong-Ren Li
- Tianjin Key Laboratory of Aqua-ecology and Aquaculture, Fisheries College, Tianjin Agricultural University, Tianjin, 300384, China
| | - Yong-Jun Guo
- Tianjin Key Laboratory of Aqua-ecology and Aquaculture, Fisheries College, Tianjin Agricultural University, Tianjin, 300384, China
| | - Tao Zhang
- CAS Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory for Marine Ecology and Environmental Science, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071, China; CAS Engineering Laboratory for Marine Ranching, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Shandong Province Key Laboratory of Experimental Marine Biology, Qingdao, 266071, China.
| | - Hao Song
- CAS Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory for Marine Ecology and Environmental Science, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071, China; CAS Engineering Laboratory for Marine Ranching, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Shandong Province Key Laboratory of Experimental Marine Biology, Qingdao, 266071, China.
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Alizadeh J, da Silva Rosa SC, Weng X, Jacobs J, Lorzadeh S, Ravandi A, Vitorino R, Pecic S, Zivkovic A, Stark H, Shojaei S, Ghavami S. Ceramides and ceramide synthases in cancer: Focus on apoptosis and autophagy. Eur J Cell Biol 2023; 102:151337. [PMID: 37392580 DOI: 10.1016/j.ejcb.2023.151337] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 05/18/2023] [Accepted: 06/23/2023] [Indexed: 07/03/2023] Open
Abstract
Different studies corroborate a role for ceramide synthases and their downstream products, ceramides, in modulation of apoptosis and autophagy in the context of cancer. These mechanisms of regulation, however, appear to be context dependent in terms of ceramides' fatty acid chain length, subcellular localization, and the presence or absence of their downstream targets. Our current understanding of the role of ceramide synthases and ceramides in regulation of apoptosis and autophagy could be harnessed to pioneer the development of new treatments to activate or inhibit a single type of ceramide synthase, thereby regulating the apoptosis induction or cross talk of apoptosis and autophagy in cancer cells. Moreover, the apoptotic function of ceramide suggests that ceramide analogues can pave the way for the development of novel cancer treatments. Therefore, in the current review paper we discuss the impact of ceramide synthases and ceramides in regulation of apoptosis and autophagy in context of different types of cancers. We also briefly introduce the latest information on ceramide synthase inhibitors, their application in diseases including cancer therapy, and discuss approaches for drug discovery in the field of ceramide synthase inhibitors. We finally discussed strategies for developing strategies to use lipids and ceramides analysis in biological fluids for developing early biomarkers for cancer.
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Affiliation(s)
- Javad Alizadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Simone C da Silva Rosa
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Xiaohui Weng
- Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA 92834, United States
| | - Joadi Jacobs
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Amir Ravandi
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, 66 Chancellors Cir, Winnipeg, MB R3T 2N2, Canada
| | - Rui Vitorino
- UnIC, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; Department of Medical Sciences, Institute of Biomedicine iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Stevan Pecic
- Department of Chemistry & Biochemistry, California State University, Fullerton, 800 N. State College, Fullerton, CA 92834, United States
| | - Aleksandra Zivkovic
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetstrasse 1, 40225 Duesseldorf, Germany
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetstrasse 1, 40225 Duesseldorf, Germany
| | - Shahla Shojaei
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, 41-800 Zabrze, Poland; Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, MB R3T 2N2, Canada.
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25
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Abstract
Maintenance of protein homeostasis and organelle integrity and function is critical for cellular homeostasis and cell viability. Autophagy is the principal mechanism that mediates the delivery of various cellular cargoes to lysosomes for degradation and recycling. A myriad of studies demonstrate important protective roles for autophagy against disease. However, in cancer, seemingly opposing roles of autophagy are observed in the prevention of early tumour development versus the maintenance and metabolic adaptation of established and metastasizing tumours. Recent studies have addressed not only the tumour cell intrinsic functions of autophagy, but also the roles of autophagy in the tumour microenvironment and associated immune cells. In addition, various autophagy-related pathways have been described, which are distinct from classical autophagy, that utilize parts of the autophagic machinery and can potentially contribute to malignant disease. Growing evidence on how autophagy and related processes affect cancer development and progression has helped guide efforts to design anticancer treatments based on inhibition or promotion of autophagy. In this Review, we discuss and dissect these different functions of autophagy and autophagy-related processes during tumour development, maintenance and progression. We outline recent findings regarding the role of these processes in both the tumour cells and the tumour microenvironment and describe advances in therapy aimed at autophagy processes in cancer.
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Affiliation(s)
- Jayanta Debnath
- Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
| | - Noor Gammoh
- MRC Institute of Genetics & Cancer, The University of Edinburgh, Edinburgh, UK.
| | - Kevin M Ryan
- Cancer Research UK Beatson Institute, Glasgow, UK.
- School of Cancer Sciences, University of Glasgow, Glasgow, UK.
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26
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Xiao C, Xiong W, Xu Y, Zou J, Zeng Y, Liu J, Peng Y, Hu C, Wu F. Immunometabolism: a new dimension in immunotherapy resistance. Front Med 2023; 17:585-616. [PMID: 37725232 DOI: 10.1007/s11684-023-1012-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 05/19/2023] [Indexed: 09/21/2023]
Abstract
Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.
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Affiliation(s)
- Chaoyue Xiao
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, China
| | - Yiting Xu
- Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Ji'an Zou
- Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Yue Zeng
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Junqi Liu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yurong Peng
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Chunhong Hu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Hunan Cancer Mega-Data Intelligent Application and Engineering Research Centre, Changsha, 410011, China
| | - Fang Wu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
- Hunan Cancer Mega-Data Intelligent Application and Engineering Research Centre, Changsha, 410011, China.
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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27
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Pan Y, Qiu D, Chen S, Han X, Li R. High glucose inhibits neural differentiation by excessive autophagy <em>via</em> peroxisome proliferator-activated receptor gamma. Eur J Histochem 2023; 67. [PMID: 37170914 DOI: 10.4081/ejh.2023.3691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/24/2023] [Indexed: 05/13/2023] Open
Abstract
The high prevalence of prediabetes and diabetes globally has led to the widespread occurrence of severe complications, such as diabetic neuropathy, which is a result of chronic hyperglycemia. Studies have demonstrated that maternal diabetes can lead to neural tube defects by suppressing neurogenesis during neuroepithelium development. While aberrant autophagy has been associated with abnormal neuronal differentiation, the mechanism by which high glucose suppresses neural differentiation in stem cells remains unclear. Therefore, we developed a neuronal cell differentiation model of retinoic acid induced P19 cells to investigate the impact of high glucose on neuronal differentiation in vitro. Our findings indicate that high glucose (HG) hinders neuronal differentiation and triggers excessive. Furthermore, HG treatment significantly reduces the expression of markers for neurons (Tuj1) and glia (GFAP), while enhancing autophagic activity mediated by peroxisome proliferator-activated receptor gamma (PPARγ). By manipulating PPARγ activity through pharmacological approaches and genetically knocking it down using shRNA, we discovered that altering PPARγ activity affects the differentiation of neural stem cells exposed to HG. Our study reveals that PPARγ acts as a downstream mediator in high glucose-suppressed neural stem cell differentiation and that refining autophagic activity via PPARγ at an appropriate level could improve neuronal differentiation efficiency. Our data provide novel insights and potential therapeutic targets for the clinical management of gestational diabetes mellitus.
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Affiliation(s)
- Yin Pan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Jinan, Guangzhou.
| | - Di Qiu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Jinan, Guangzhou.
| | - Shu Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Jinan, Guangzhou.
| | - Xiaoxue Han
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Jinan, Guangzhou.
| | - Ruiman Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Jinan, Guangzhou.
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28
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Sharma A, Anand SK, Singh N, Dwivedi UN, Kakkar P. AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis. Exp Cell Res 2023; 428:113614. [PMID: 37127064 DOI: 10.1016/j.yexcr.2023.113614] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/18/2023] [Accepted: 04/22/2023] [Indexed: 05/03/2023]
Abstract
Cells are programmed to favorably respond towards the nutrient availability by adapting their metabolism to meet energy demands. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine energy-sensing kinase. It gets activated upon a decrease in the cellular energy status as reflected by an increased AMP/ATP ratio, ADP, and also during the conditions of glucose starvation without change in the adenine nucelotide ratio. AMPK functions as a centralized regulator of metabolism, acting at cellular and physiological levels to circumvent the metabolic stress by restoring energy balance. This review intricately highlights the integrated signaling pathways by which AMPK gets activated allosterically or by multiple non-canonical upstream kinases. AMPK activates the ATP generating processes (e.g., fatty acid oxidation) and inhibits the ATP consuming processes that are non-critical for survival (e.g., cell proliferation, protein and triglyceride synthesis). An integrated signaling network with AMPK as the central effector regulates all the aspects of enhanced stress resistance, qualified cellular housekeeping, and energy metabolic homeostasis. Importantly, the AMPK mediated amelioration of cellular stress and inflammatory responses are mediated by stimulation of transcription factors such as Nrf2, SIRT1, FoxO and inhibition of NF-κB serving as main downstream effectors. Moreover, many lines of evidence have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling to fine-tune the metabolic pathways in response to different cellular signals. This review also highlights the critical involvement of AMPK in promoting mitochondrial health, and homeostasis, including mitophagy. Loss of AMPK or ULK1 activity leads to aberrant accumulation of autophagy-related proteins and defective mitophagy thus, connecting cellular energy sensing to autophagy and mitophagy.
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Affiliation(s)
- Ankita Sharma
- Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, India; Department of Biochemistry, University of Lucknow, Lucknow, 226007, India; Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Bijnor-Sisendi Road, Post Office Mati, Lucknow, 226002, India.
| | - Sumit Kr Anand
- Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Department of Pathology, LSU Health, 1501 Kings Hwy, Shreveport, LA, 71103, USA.
| | - Neha Singh
- Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
| | | | - Poonam Kakkar
- Herbal Research Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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29
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Esteves AR, Silva DF, Banha D, Candeias E, Guedes B, Cardoso SM. LPS-induced mitochondrial dysfunction regulates innate immunity activation and α-synuclein oligomerization in Parkinson's disease. Redox Biol 2023; 63:102714. [PMID: 37120929 PMCID: PMC10172719 DOI: 10.1016/j.redox.2023.102714] [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: 03/27/2023] [Revised: 04/23/2023] [Accepted: 04/23/2023] [Indexed: 05/02/2023] Open
Abstract
Sporadic Parkinson's disease (sPD) is a complex multifactorial disorder which etiology remains elusive. Several mechanisms have been described to contribute to PD development namely mitochondrial dysfunction, activation of inflammatory pathways and the deposition of unfolded proteins such as α-synuclein. Our work shows for the first time that lipopolysaccharide (LPS)-induced activation of innate immunity requires a functional mitochondria and mimics PD pathology in cells. We found in primary mesencephalic neurons that LPS targeted the mitochondria and activated neuronal innate immune responses, which culminated with α-synuclein oligomerization. Moreover, in cybrid cell lines repopulated with mtDNA from sPD subjects with inherent mitochondrial dysfunction and NT2-Rho0 obtained by long-term ethidium bromide exposure, and so without a functional mitochondrial, LPS was not able to further activate innate immunity or increase α-synuclein aggregation. Herein, we showed that mesencephalic neurons are able to activate innate immunity after LPS exposure and this pathway is dependent on mitochondria. Moreover, we disclose that α-synuclein over production is an innate immune response. Our data indicate that mitochondria provide the base for innate immunity activation in idiopathic PD.
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Affiliation(s)
- A Raquel Esteves
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
| | - Diana F Silva
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
| | - Diogo Banha
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
| | - Emanuel Candeias
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Beatriz Guedes
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
| | - Sandra M Cardoso
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute of Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
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30
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Mordecai J, Ullah S, Ahmad I. Sulforaphane and Its Protective Role in Prostate Cancer: A Mechanistic Approach. Int J Mol Sci 2023; 24:ijms24086979. [PMID: 37108142 PMCID: PMC10138336 DOI: 10.3390/ijms24086979] [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: 03/16/2023] [Revised: 04/08/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
The increasing incidence of prostate cancer worldwide has spurred research into novel therapeutics for its treatment and prevention. Sulforaphane, derived from broccoli and other members of the Brassica genus, is a phytochemical shown to have anticancer properties. Numerous studies have shown that sulforaphane prevents the development and progression of prostatic tumors. This review evaluates the most recent published reports on prevention of the progression of prostate cancer by sulforaphane in vitro, in vivo and in clinical settings. A detailed description of the proposed mechanisms of action of sulforaphane on prostatic cells is provided. Furthermore, we discuss the challenges, limitations and future prospects of using sulforaphane as a therapeutic agent in treatment of prostate cancer.
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Affiliation(s)
- James Mordecai
- Department of Bioengineering, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran 31261, Saudi Arabia
| | - Saleem Ullah
- Department of Transdisciplinary Science and Engineering, School of Environment and Society, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
| | - Irshad Ahmad
- Department of Bioengineering, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran 31261, Saudi Arabia
- Interdisciplinary Research Center for Membranes and Water Security, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran 31261, Saudi Arabia
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31
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Zhong Y, Tang K, Nattel S, Zhai M, Gong S, Yu Q, Zeng Y, E G, Maimaitiaili N, Wang J, Xu Y, Peng W, Li H. Myosin light-chain 4 gene-transfer attenuates atrial fibrosis while correcting autophagic flux dysregulation. Redox Biol 2023; 60:102606. [PMID: 36645977 PMCID: PMC9860351 DOI: 10.1016/j.redox.2023.102606] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 01/12/2023] Open
Abstract
OBJECTIVES To determine the role of MYL4 regulation of lysosomal function and its disturbance in fibrotic atrial cardiomyopathy. BACKGROUND We have previously demonstrated that the atrial-specific essential light chain protein MYL4 is required for atrial contractile, electrical, and structural integrity. MYL4 mutation/dysfunction leads to atrial fibrosis, standstill, and dysrhythmia. However, the underlying pathogenic mechanisms remain unclear. METHODS AND RESULTS Rats subjected to knock-in of a pathogenic MYL4 mutant (p.E11K) developed fibrotic atrial cardiomyopathy. Proteome analysis and single-cell RNA sequencing indicate enrichment of autophagy pathways in mutant-MYL4 atrial dysfunction. Immunofluorescence and electron microscopy revealed undegraded autophagic vesicles accumulated in MYL4p.E11K rat atrium. Next, we identified that dysfunctional MYL4 protein impairs autophagy flux in vitro and in vivo. Cardiac lysosome positioning and mobility were regulated by MYL4 in cardiomyocytes, which affected lysosomal acidification and maturation of lysosomal cathepsins. We then examined the effects of MYL4 overexpression via adenoviral gene-transfer on atrial cardiomyopathy induced by MYL4 mutation: MYL4 protein overexpression attenuated atrial structural remodeling and autophagy dysfunction. CONCLUSIONS MYL4 regulates autophagic flux in atrial cardiomyocytes via lysosomal mobility. MYL4 overexpression attenuates MYL4 p.E11K induced fibrotic atrial cardiomyopathy, while correcting autophagy and lysosomal function. These results provide a molecular basis for MYL4-mutant induced fibrotic atrial cardiomyopathy and identify a potential biological-therapy approach for the treatment of atrial fibrosis.
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Affiliation(s)
- Yuan Zhong
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kai Tang
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Stanley Nattel
- Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada; Université de Montréal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany; HIU LYRIC and Fondation Bordeaux Université de Bordeaux, France
| | - Ming Zhai
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shiyu Gong
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qing Yu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yanxi Zeng
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guangxi E
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Nuerbiyemu Maimaitiaili
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jun Wang
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yawei Xu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Wenhui Peng
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Hailing Li
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
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32
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Liu ZJ, Zhu CF. Causal relationship between insulin resistance and sarcopenia. Diabetol Metab Syndr 2023; 15:46. [PMID: 36918975 PMCID: PMC10015682 DOI: 10.1186/s13098-023-01022-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/08/2023] [Indexed: 03/15/2023] Open
Abstract
Sarcopenia is a multifactorial disease characterized by reduced muscle mass and function, leading to disability, death, and other diseases. Recently, the prevalence of sarcopenia increased considerably, posing a serious threat to health worldwide. However, no clear international consensus has been reached regarding the etiology of sarcopenia. Several studies have shown that insulin resistance may be an important mechanism in the pathogenesis of induced muscle attenuation and that, conversely, sarcopenia can lead to insulin resistance. However, the causal relationship between the two is not clear. In this paper, the pathogenesis of sarcopenia is analyzed, the possible intrinsic causal relationship between sarcopenia and insulin resistance examined, and research progress expounded to provide a basis for the clinical diagnosis, treatment, and study of the mechanism of sarcopenia.
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Affiliation(s)
- Zi-jian Liu
- Shenzhen Clinical Medical College, Southern Medical University, Guangdong, 518101 China
| | - Cui-feng Zhu
- Shenzhen Hospital of Southern Medical University, Guangdong, 518101 China
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33
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Takenaka T, Ohnishi Y, Yamamoto M, Setoyama D, Kishima H. Glycolytic System in Axons Supplement Decreased ATP Levels after Axotomy of the Peripheral Nerve. eNeuro 2023; 10:ENEURO.0353-22.2023. [PMID: 36894321 PMCID: PMC10035771 DOI: 10.1523/eneuro.0353-22.2023] [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: 08/30/2022] [Revised: 02/04/2023] [Accepted: 02/25/2023] [Indexed: 03/11/2023] Open
Abstract
Wallerian degeneration (WD) occurs in the early stages of numerous neurologic disorders, and clarifying WD pathology is crucial for the advancement of neurologic therapies. ATP is acknowledged as one of the key pathologic substances in WD. The ATP-related pathologic pathways that regulate WD have been defined. The elevation of ATP levels in axon contributes to delay WD and protects axons. However, ATP is necessary for the active processes to proceed WD, given that WD is stringently managed by auto-destruction programs. But little is known about the bioenergetics during WD. In this study, we made sciatic nerve transection models for GO-ATeam2 knock-in rats and mice. We presented the spatiotemporal ATP distribution in the injured axons with in vivo ATP imaging systems, and investigated the metabolic source of ATP in the distal nerve stump. A gradual decrease in ATP levels was observed before the progression of WD. In addition, the glycolytic system and monocarboxylate transporters (MCTs) were activated in Schwann cells following axotomy. Interestingly, in axons, we found the activation of glycolytic system and the inactivation of the tricarboxylic acid (TCA) cycle. Glycolytic inhibitors, 2-deoxyglucose (2-DG) and MCT inhibitors, a-cyano-4-hydroxycinnamic acid (4-CIN) decreased ATP and enhanced WD progression, whereas mitochondrial pyruvate carrier (MPC) inhibitors (MSDC-0160) did not change. Finally, ethyl pyruvate (EP) increased ATP levels and delayed WD. Together, our findings suggest that glycolytic system, both in Schwann cells and axons, is the main source of maintaining ATP levels in the distal nerve stump.
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Affiliation(s)
- Tomofumi Takenaka
- Department of neurosurgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
- Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
| | - Yuichiro Ohnishi
- Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
- Department of Neurosurgery, Osaka Gyoumeikan Hospital, Osaka, 554-0012, Japan
| | - Masamichi Yamamoto
- Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan
| | - Daiki Setoyama
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Haruhiko Kishima
- Department of neurosurgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
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34
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Li J, Gong SH, He YL, Cao Y, Chen Y, Huang GH, Wang YF, Zhao M, Cheng X, Zhou YZ, Zhao T, Zhao YQ, Fan M, Wu HT, Zhu LL, Wu LY. Autophagy Is Essential for Neural Stem Cell Proliferation Promoted by Hypoxia. Stem Cells 2023; 41:77-92. [PMID: 36208284 DOI: 10.1093/stmcls/sxac076] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 09/06/2022] [Indexed: 02/02/2023]
Abstract
Hypoxia as a microenvironment or niche stimulates proliferation of neural stem cells (NSCs). However, the underlying mechanisms remain elusive. Autophagy is a protective mechanism by which recycled cellular components and energy are rapidly supplied to the cell under stress. Whether autophagy mediates the proliferation of NSCs under hypoxia and how hypoxia induces autophagy remain unclear. Here, we report that hypoxia facilitates embryonic NSC proliferation through HIF-1/mTORC1 signaling pathway-mediated autophagy. Initially, we found that hypoxia greatly induced autophagy in NSCs, while inhibition of autophagy severely impeded the proliferation of NSCs in hypoxia conditions. Next, we demonstrated that the hypoxia core regulator HIF-1 was necessary and sufficient for autophagy induction in NSCs. Considering that mTORC1 is a key switch that suppresses autophagy, we subsequently analyzed the effect of HIF-1 on mTORC1 activity. Our results showed that the mTORC1 activity was negatively regulated by HIF-1. Finally, we provided evidence that HIF-1 regulated mTORC1 activity via its downstream target gene BNIP3. The increased expression of BNIP3 under hypoxia enhanced autophagy activity and proliferation of NSCs, which was mediated by repressing the activity of mTORC1. We further illustrated that BNIP3 can interact with Rheb, a canonical activator of mTORC1. Thus, we suppose that the interaction of BNIP3 with Rheb reduces the regulation of Rheb toward mTORC1 activity, which relieves the suppression of mTORC1 on autophagy, thereby promoting the rapid proliferation of NSCs. Altogether, this study identified a new HIF-1/BNIP3-Rheb/mTORC1 signaling axis, which regulates the NSC proliferation under hypoxia through induction of autophagy.
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Affiliation(s)
- Jian Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
| | - Sheng-Hui Gong
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Yun-Ling He
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Yan Cao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
| | - Ying Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
| | - Guang-Hai Huang
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Yu-Fei Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
| | - Ming Zhao
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Xiang Cheng
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Yan-Zhao Zhou
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Tong Zhao
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Yong-Qi Zhao
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Ming Fan
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Hai-Tao Wu
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Ling-Ling Zhu
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China.,Department of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, People's Republic of China.,Department of Pharmacology, University of Nanhua, Hengyang, China
| | - Li-Ying Wu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.,Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
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Nie Z, Zhu S, Wu L, Sun R, Shu J, He Y, Feng H. Progress on innate immune evasion and live attenuated vaccine of pseudorabies virus. Front Microbiol 2023; 14:1138016. [PMID: 36937252 PMCID: PMC10020201 DOI: 10.3389/fmicb.2023.1138016] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Pseudorabies virus (PRV) is a highly infectious disease that can infect most mammals, with pigs as the only natural host, has caused considerable economic losses to the pig husbandry of the world. Innate immunity is the first defense line of the host against the attack of pathogens and is essential for the proper establishment of adaptive immunity. The host uses the innate immune response to against the invasion of PRV; however PRV makes use of various strategies to inhibit the innate immunity to promote the virus replication. Currently, live attenuated vaccine is used to prevent pig from infection with the PRV worldwide, such as Bartha K61. However, a growing number of data indicates that these vaccines do not provide complete protection against new PRV variants that have emerged since late 2011. Here we summarized the interactions between PRV and host innate immunity and the current status of live attenuated PRV vaccines to promote the development of novel and more effective PRV vaccines.
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Affiliation(s)
- Zhenyu Nie
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
- Shaoxing Academy of Biomedicine, Zhejiang Sci-Tech University, Shaoxing, China
| | - Shunfan Zhu
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
- Shaoxing Academy of Biomedicine, Zhejiang Sci-Tech University, Shaoxing, China
| | - Li Wu
- Department of Biology, College of Life Sciences, China Jiliang University, Hangzhou, China
| | - Ruolin Sun
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Jianhong Shu
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yulong He
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Huapeng Feng
- Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
- *Correspondence: Huapeng Feng,
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36
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Chen M, Zhang H, Chu YH, Tang Y, Pang XW, Qin C, Tian DS. Microglial autophagy in cerebrovascular diseases. Front Aging Neurosci 2022; 14:1023679. [PMID: 36275005 PMCID: PMC9582432 DOI: 10.3389/fnagi.2022.1023679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 09/20/2022] [Indexed: 11/25/2022] Open
Abstract
Microglia are considered core regulators for monitoring homeostasis in the brain and primary responders to central nervous system (CNS) injuries. Autophagy affects the innate immune functions of microglia. Recently some evidence suggests that microglial autophagy is closely associated with brain function in both ischemic stroke and hemorrhagic stroke. Herein, we will discuss the interaction between autophagy and other biological processes in microglia under physiological and pathological conditions and highlight the interaction between microglial metabolism and autophagy. In the end, we focus on the effect of microglial autophagy in cerebrovascular diseases.
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37
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Steenwinkel TE, Hamre KK, Werner T. The use of non-model Drosophila species to study natural variation in TOR pathway signaling. PLoS One 2022; 17:e0270436. [PMID: 36137094 PMCID: PMC9499319 DOI: 10.1371/journal.pone.0270436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/06/2022] [Indexed: 11/25/2022] Open
Abstract
Nutrition and growth are strongly linked, but not much is known about how nutrition leads to growth. To understand the connection between nutrition through the diet, growth, and proliferation, we need to study the phenotypes resulting from the activation and inhibition of central metabolic pathways. One of the most highly conserved metabolic pathways across eukaryotes is the Target of Rapamycin (TOR) pathway, whose primary role is to detect the availability of nutrients and to either induce or halt cellular growth. Here we used the model organism Drosophila melanogaster (D. mel.) and three non-model Drosophila species with different dietary needs, Drosophila guttifera (D. gut.), Drosophila deflecta (D. def.), and Drosophila tripunctata (D. tri.), to study the effects of dietary amino acid availability on fecundity and longevity. In addition, we inhibited the Target of Rapamycin (TOR) pathway, using rapamycin, to test how the inhibition interplays with the nutritional stimuli in these four fruit fly species. We hypothesized that the inhibition of the TOR pathway would reverse the phenotypes observed under conditions of overfeeding. Our results show that female fecundity increased with higher yeast availability in all four species but decreased in response to TOR inhibition. The longevity data were more varied: most species experienced an increase in median lifespan in both genders with an increase in yeast availability, while the lifespan of D. mel. females decreased. When exposed to the TOR inhibitor rapamycin, the life spans of most species decreased, except for D. tri, while we observed a major reduction in fecundity across all species. The obtained data can benefit future studies on the evolution of metabolism by showing the potential of using non-model species to track changes in metabolism. Particularly, our data show the possibility to use relatively closely related Drosophila species to gain insight on the evolution of TOR signaling.
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Affiliation(s)
- Tessa E. Steenwinkel
- Department of Biological Sciences, Michigan Technological University, Houghton, Michigan, United States of America
| | - Kailee K. Hamre
- Department of Biological Sciences, Michigan Technological University, Houghton, Michigan, United States of America
| | - Thomas Werner
- Department of Biological Sciences, Michigan Technological University, Houghton, Michigan, United States of America
- * E-mail:
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38
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Qi YL, Wang HR, Chen LL, Duan YT, Yang SY, Zhu HL. Recent advances in small-molecule fluorescent probes for studying ferroptosis. Chem Soc Rev 2022; 51:7752-7778. [PMID: 36052828 DOI: 10.1039/d1cs01167g] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Ferroptosis is an iron-dependent, non-apoptotic form of programmed cell death driven by excessive lipid peroxidation (LPO). Mounting evidence suggests that the unique modality of cell death is involved in the development and progression of several diseases including cancer, cardiovascular diseases (CVDs), neurodegenerative disorders, etc. However, the pathogenesis and signalling pathways of ferroptosis are not fully understood, possibly due to the lack of robust tools for the highly selective and sensitive imaging of ferroptosis analytes in complex living systems. Up to now, various small-molecule fluorescent probes have been applied as promising chemosensors for studying ferroptosis through tracking the biomolecules or microenvironment-related parameters in vitro and in vivo. In this review, we comprehensively reviewed the recent development of small-molecule fluorescent probes for studying ferroptosis, with a focus on the analytes, design strategies and bioimaging applications. We also provided new insights to overcome the major challenges in this emerging field.
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Affiliation(s)
- Ya-Lin Qi
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China. .,Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.,State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.,Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA.
| | - Hai-Rong Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Li-Li Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Yong-Tao Duan
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China. .,Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China
| | - Sheng-Yu Yang
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA.
| | - Hai-Liang Zhu
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China. .,Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.,State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
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39
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Li J, Quan C, He YL, Cao Y, Chen Y, Wang YF, Wu LY. Autophagy regulated by the HIF/REDD1/mTORC1 signaling is progressively increased during erythroid differentiation under hypoxia. Front Cell Dev Biol 2022; 10:896893. [PMID: 36092719 PMCID: PMC9448881 DOI: 10.3389/fcell.2022.896893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 08/04/2022] [Indexed: 11/13/2022] Open
Abstract
For hematopoietic stem and progenitor cells (HSPCs), hypoxia is a specific microenvironment known as the hypoxic niche. How hypoxia regulates erythroid differentiation of HSPCs remains unclear. In this study, we show that hypoxia evidently accelerates erythroid differentiation, and autophagy plays a pivotal role in this process. We further determine that mTORC1 signaling is suppressed by hypoxia to relieve its inhibition of autophagy, and with the process of erythroid differentiation, mTORC1 activity gradually decreases and autophagy activity increases accordingly. Moreover, we provide evidence that the HIF-1 target gene REDD1 is upregulated to suppress mTORC1 signaling and enhance autophagy, thereby promoting erythroid differentiation under hypoxia. Together, our study identifies that the enhanced autophagy by hypoxia favors erythroid maturation and elucidates a new regulatory pattern whereby autophagy is progressively increased during erythroid differentiation, which is driven by the HIF-1/REDD1/mTORC1 signaling in a hypoxic niche.
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40
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Ghavami S, Zamani M, Ahmadi M, Erfani M, Dastghaib S, Darbandi M, Darbandi S, Vakili O, Siri M, Grabarek BO, Boroń D, Zarghooni M, Wiechec E, Mokarram P. Epigenetic regulation of autophagy in gastrointestinal cancers. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166512. [PMID: 35931405 DOI: 10.1016/j.bbadis.2022.166512] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 07/11/2022] [Accepted: 07/28/2022] [Indexed: 11/09/2022]
Abstract
The development of novel therapeutic approaches is necessary to manage gastrointestinal cancers (GICs). Considering the effective molecular mechanisms involved in tumor growth, the therapeutic response is pivotal in this process. Autophagy is a highly conserved catabolic process that acts as a double-edged sword in tumorigenesis and tumor inhibition in a context-dependent manner. Depending on the stage of malignancy and cellular origin of the tumor, autophagy might result in cancer cell survival or death during the GICs' progression. Moreover, autophagy can prevent the progression of GIC in the early stages but leads to chemoresistance in advanced stages. Therefore, targeting specific arms of autophagy could be a promising strategy in the prevention of chemoresistance and treatment of GIC. It has been revealed that autophagy is a cytoplasmic event that is subject to transcriptional and epigenetic regulation inside the nucleus. The effect of epigenetic regulation (including DNA methylation, histone modification, and expression of non-coding RNAs (ncRNAs) in cellular fate is still not completely understood. Recent findings have indicated that epigenetic alterations can modify several genes and modulators, eventually leading to inhibition or promotion of autophagy in different cancer stages, and mediating chemoresistance or chemosensitivity. The current review focuses on the links between autophagy and epigenetics in GICs and discusses: 1) How autophagy and epigenetics are linked in GICs, by considering different epigenetic mechanisms; 2) how epigenetics may be involved in the alteration of cancer-related phenotypes, including cell proliferation, invasion, and migration; and 3) how epidrugs modulate autophagy in GICs to overcome chemoresistance.
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Affiliation(s)
- Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Hematology and Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland.
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Mehran Erfani
- Department of Biochemistry, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Sara Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Morvarid Siri
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Beniamin Oskar Grabarek
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Dariusz Boroń
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Maryam Zarghooni
- Department of Laboratory Medicine and Pathobiology, University of Toronto Alumni, Toronto, Canada
| | - Emilia Wiechec
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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Park SW, Kim J, Oh S, Lee J, Cha J, Lee HS, Kim KI, Park D, Baek SH. PHF20 is crucial for epigenetic control of starvation-induced autophagy through enhancer activation. Nucleic Acids Res 2022; 50:7856-7872. [PMID: 35821310 PMCID: PMC9371932 DOI: 10.1093/nar/gkac584] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/15/2022] [Accepted: 06/23/2022] [Indexed: 11/13/2022] Open
Abstract
Autophagy is a catabolic pathway that maintains cellular homeostasis under various stress conditions, including conditions of nutrient deprivation. To elevate autophagic flux to a sufficient level under stress conditions, transcriptional activation of autophagy genes occurs to replenish autophagy components. Thus, the transcriptional and epigenetic control of the genes regulating autophagy is essential for cellular homeostasis. Here, we applied integrated transcriptomic and epigenomic profiling to reveal the roles of plant homeodomain finger protein 20 (PHF20), which is an epigenetic reader possessing methyl binding activity, in controlling the expression of autophagy genes. Phf20 deficiency led to impaired autophagic flux and autophagy gene expression under glucose starvation. Interestingly, the genome-wide characterization of chromatin states by Assay for Transposase-Accessible Chromatin (ATAC)-sequencing revealed that the PHF20-dependent chromatin remodelling occurs in enhancers that are co-occupied by dimethylated lysine 36 on histone H3 (H3K36me2). Importantly, the recognition of H3K36me2 by PHF20 was found to be highly correlated with increased levels of H3K4me1/2 at the enhancer regions. Collectively, these results indicate that PHF20 regulates autophagy genes through enhancer activation via H3K36me2 recognition as an epigenetic reader. Our findings emphasize the importance of nuclear events in the regulation of autophagy.
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Affiliation(s)
- Se Won Park
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Jaehoon Kim
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea
| | - Sungryong Oh
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Jeongyoon Lee
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Joowon Cha
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Hyun Sik Lee
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Keun Il Kim
- Department of Biological Sciences, Sookmyung Women's University, Seoul 04310, South Korea
| | - Daechan Park
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea.,Department of Biological Sciences, Ajou University, Suwon 16499, South Korea
| | - Sung Hee Baek
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea
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Cao Z, Guan L, Yu R, Chen J. Identifying Autophagy-Related lncRNAs and Potential ceRNA Networks in NAFLD. Front Genet 2022; 13:931928. [PMID: 35846147 PMCID: PMC9279897 DOI: 10.3389/fgene.2022.931928] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease with complex pathogenesis, which brings economic burden to the society, and there is still no effective therapy. Impaired autophagy has been implicated in the development of NAFLD. Long noncoding RNAs (lncRNAs) are also reported to play a role in the pathogenesis of NAFLD. However, the role of autophagy-related lncRNAs in NAFLD disease has not been elucidated. Here, we mined GSE135251, GSE160016, GSE130970 and GSE185062 datasets from the Gene Expression Omnibus database (GEO) and obtained the human autophagy-related gene list from the Human Autophagy Database (HADb) for in-depth bioinformatic analysis. Following differential expression analysis and intersection of the datasets, Pearson correlation analysis was performed on DElncRNAs and autophagy-related DEmRNAs to obtain autophagy-related lncRNAs, and then Starbase3.0 and TargetScan7.2 were used to construct competing endogenous RNAs (ceRNA) regulatory networks. We constructed four lncRNA-dominated ceRNA regulatory networks (PSMG3-AS1, MIRLET7BHG, RP11-136K7.2, LINC00925), and visualized with Cytoscape. Then we performed co-expression analysis of the ceRNA networks and autophagy-related genes, and functionally annotated them with Metascape. Finally, we performed receiver operating characteristic curve (ROC) analysis on lncRNAs and mRNAs within the ceRNA networks. Conclusively, our project is the first to study autophagy-related lncRNAs in NAFLD and finally mined four autophagy-related lncRNAs (PSMG3-AS1, MIRLET7BHG, RP11-136K7.2, LINC00925). We suggested that the four autophagy-related lncRNAs may be closely associated with the occurrence and development of NAFLD through the corresponding ceRNA regulatory networks. This research brings new horizons to the study of NAFLD.
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Agrawal Y, Sharma T, Islam S, Nadkarni KS, Santra MK. F-box protein FBXO41 suppresses breast cancer growth by inducing autophagic cell death through facilitating proteasomal degradation of oncogene SKP2. Int J Biochem Cell Biol 2022; 147:106228. [PMID: 35598880 DOI: 10.1016/j.biocel.2022.106228] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/12/2022] [Accepted: 05/15/2022] [Indexed: 12/30/2022]
Abstract
F-box proteins form SCF (Cullin1, SKP1 and F-box-protein) ubiquitin ligase complexes to ubiquitinate cellular proteins. They play key role in several biological processes, including cell cycle progression, cellular signaling, stress response and cell death pathways. Therefore, deregulation of F-box proteins is closely associated with cancer progression. However, the role of most of the F-box proteins, including FBXO41, in cancer progression remains elusive. Here, we unravel the role of FBXO41 in cancer progression. We show that FBXO41 suppresses cancer cell proliferation and tumor growth by inducing autophagic cell death through an alternative pathway. Results revealed that FBXO41-mediated autophagic cell death induction is dependent on accumulation of cell cycle checkpoint protein p21. We found that FBXO41 increases the expression levels of p21 at the post-translational level by promoting the proteasomal degradation of SKP2, an oncogenic F-box protein. Mechanistically, FBXO41 along with p21 disrupts the inhibitory BCL2 (anti-apoptotic protein)-Beclin1 (autophagy initiating factor) complex of autophagy induction to release Beclin1, thereby inducing autophagy. Overall, the present study establishes a new FBXO41-SKP2-p21 axis for induction of autophagic cell death to prevent cancer growth, which could be explored to develop promising cancer therapeutics.
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Affiliation(s)
- Yashika Agrawal
- Molecular Oncology Laboratory, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra 411007, India; Department of Biotechnology, S. P. Pune University, Ganeshkhind Road, Pune, Maharashtra, 411007 India
| | - Tanisha Sharma
- Molecular Oncology Laboratory, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra 411007, India; Department of Biotechnology, S. P. Pune University, Ganeshkhind Road, Pune, Maharashtra, 411007 India
| | - Sehbanul Islam
- Molecular Oncology Laboratory, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra 411007, India
| | - Kaustubh S Nadkarni
- Molecular Oncology Laboratory, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra 411007, India; Department of Biotechnology, S. P. Pune University, Ganeshkhind Road, Pune, Maharashtra, 411007 India
| | - Manas Kumar Santra
- Molecular Oncology Laboratory, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra 411007, India.
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Chen E, Chang H, Gao R, Qiu Y, Chen H, Cheng X, Gan L, Ye-Lehmann S, Zhu T, Liu J, Chen G, Chen C. Poly(I:C) attenuates myocardial ischemia/reperfusion injury by restoring autophagic function. FASEB J 2022; 36:e22317. [PMID: 35438806 DOI: 10.1096/fj.202101220rr] [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: 07/30/2021] [Revised: 03/02/2022] [Accepted: 04/04/2022] [Indexed: 02/05/2023]
Abstract
Polyinosinic-polycytidylic acid (poly(I:C)) is the agonist of Toll-like receptor 3 (TLR3), which participates in innate immune responses under the condition of myocardial ischemia/reperfusion injury (MIRI). It has been shown that poly(I:C) exhibited cardioprotective activities through the PI3K/Akt pathway, which is the main signal transduction pathway during autophagy. However, the precise mechanism by whether poly(I:C) regulates autophagy remains poorly understood. Thus, this study was designed to investigate the therapeutic effect of poly(I:C) against MIRI and the underlying pathway connection with autophagy. We demonstrated that 1.25 and 5 mg/kg poly(I:C) preconditioning significantly reduced myocardial infarct size and cardiac dysfunction. Moreover, poly(I:C) significantly promoted cell survival by restoring autophagy flux and then regulating it to an adequate level Increased autophagy protein Beclin1 and LC3II together with p62 degradation after additional chloroquine. In addition, mRFP-GFP-LC3 adenoviruses exhibited autophagy activity in neonatal rat cardiac myocytes (NRCMs). Mechanistically, poly(I:C) activated the PI3K/AKT/mTOR pathway to induce autophagy, which was abolished by LY294002 (PI3K antagonist), rapamycin (autophagy activator and mTOR inhibitor), or 3-methyladenine (autophagy inhibitor), suggesting either inhibition of the PI3K/Akt/mTOR pathway or autophagy activity interrupt the beneficial effect of poly(I:C) preconditioning. In conclusion, poly(I:C) promotes cardiomyocyte survival from ischemia/reperfusion injury by regulating autophagy via the PI3K/Akt/mTOR pathway.
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Affiliation(s)
- Erya Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Haiqing Chang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Rui Gao
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Yanhua Qiu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Hai Chen
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Xu Cheng
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Lu Gan
- Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Shixin Ye-Lehmann
- INSERM Tenured Researcher (CR)INSERM Research Unit U1195, Diseases and Hormones of the Nervous System, University of Paris-Scalay Bicêtre Hospital, Le Kremlin Bicêtre CEDEX, France
| | - Tao Zhu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Jin Liu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Guo Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
| | - Chan Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Anesthesia and Critical Care Medicine, National Clinical Research Center for Geriatrics, Translational Neuroscience Center, The Research Units of West China, Chinese Academy of Medical Science, Chengdu, China
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Lv J, Wang D, Li T. Autophagy-mediated expression clusters are involved in immunity regulation of coronary artery disease. BMC Genom Data 2022; 23:24. [PMID: 35365066 PMCID: PMC8976398 DOI: 10.1186/s12863-022-01023-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 01/03/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The association between autophagy and immunity, including infiltrating immunocytes, immune reaction gene-sets, and HLAs (human leukocyte antigen) gene, remains unclear. The present study aimed to provide a valid diagnostic tool for coronary artery disease (CAD), and explore the pathological mechanisms of CAD based on the association between autophagy and immunity. METHODS First, the overlap between differentially expressed genes (DEGs) and autophagy-related genes (ARGs) was identified. Subsequently, machine learning was conducted to screen risk genes closely related to CAD. Diverse autophagy phenotype-related clusters were identified using unsupervised clustering. The connections between different clusters and immune characteristics were evaluated as well. RESULTS The present study identified 27 differentially expressed autophagy-related genes (DEAGRs) in CAD samples compared with healthy conrtrols. A classifier constructing by 9 DEARGs was regarded as an effective diagnostic tool for CAD. Furthermore, three distinct autophagy phenotype - related clusters were identified, each cluster exhibited different immune characteristics. Finally, the gene ontology (GO) analysis of 901 autophagy phenotype-related genes showed that immune response, protein phosphorylation, and innate immune response were remarkable enrichment components. CONCLUSIONS This study identified an effective classifier constituted by 9-DEARGs that has good diagnostic performance for CAD, and revealed that autophagy and the immunity may be common critical factors in the occurrence and development of CAD.
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Affiliation(s)
- Jin Lv
- Cardiovascular Disease Center, The Central Hospital Of Enshi Tujia And Miao Autonomous Prefecture, Enshi, 445000, Hubei, China
| | - Dong Wang
- Cardiovascular Disease Center, The Central Hospital Of Enshi Tujia And Miao Autonomous Prefecture, Enshi, 445000, Hubei, China
| | - Tian Li
- Cardiovascular Disease Center, The Central Hospital Of Enshi Tujia And Miao Autonomous Prefecture, Enshi, 445000, Hubei, China.
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47
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PI3K/mTOR inhibition prevents anal cancer in mice with established low-grade anal dysplasia. Exp Mol Pathol 2022; 125:104752. [PMID: 35183509 PMCID: PMC9018484 DOI: 10.1016/j.yexmp.2022.104752] [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: 12/08/2021] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 11/20/2022]
Abstract
Low-grade anal dysplasia is a disease that can progress to high-grade anal dysplasia and eventually anal cancer if left untreated. Research has shown that low-grade anal dysplasia is marked by significant autophagic dysfunction. We hypothesized that systemic induction of autophagy, via phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibition, would be effective in preventing anal cancer development in human papillomavirus (HPV) mice (K14E6/E7) with established low-grade anal dysplasia. Mice began treatment at 15 weeks of age, when 75% of mice spontaneously develop low-grade anal dysplasia, and were divided into the following groups: no treatment, systemic LY3023414 (4.5 mg/kg, dual PI3K/mTOR inhibitor) alone, topical 7,12 dimethylbenz[a]anthracene (DMBA) alone, or systemic LY3023414 and topical DMBA. Groups were compared for final histology, PI3K activity, mTOR activity, autophagic induction (light chain 3B (LC3β)), autophagic function (p62 protein), and tumor-free survival. Untreated mice or mice treated with LY3023414 alone did not progress to cancer. There was a statistically significant decrease in the number of mice that developed histologic evidence of cancer when comparing mice that received systemic LY3203414 with topical DMBA versus those that received topical DMBA alone (p = 0.0003). PI3K and mTOR activity decreased in groups treated with systemic LY3023414 and topical DMBA as compared with those treated with topical DMBA alone (p = 0.0005 and p = 0.0271, respectively). LC3β and p62 expression was not statistically altered with systemic LY3023414 treatment. Mice developed less overt tumors and had increased tumor-free survival when treated with systemic LY3023414 in the presence of topical DMBA compared to topical DMBA alone (p = 0.0016 and p < 0.001, respectively). Systemic LY3023414 treatment is effective in anal cancer prevention in the setting of established low-grade anal dysplasia in an HPV-associated mouse model of anal cancer.
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48
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Gheyas R, Ortega-Alvarez R, Chauss D, Kantorow M, Menko AS. Suppression of PI3K signaling is linked to autophagy activation and the spatiotemporal induction of the lens organelle free zone. Exp Cell Res 2022; 412:113043. [PMID: 35101390 PMCID: PMC8859841 DOI: 10.1016/j.yexcr.2022.113043] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/03/2022] [Accepted: 01/18/2022] [Indexed: 12/12/2022]
Abstract
The terminal steps of lens cell differentiation require elimination of all organelles to create a central Organelle Free Zone (OFZ) that is required for lens function of focusing images on the retina. Previous studies show that the spatiotemporal elimination of these organelles during development is autophagy-dependent. We now show that the inhibition of PI3K signaling in lens organ culture results in the premature induction of autophagy within 24 h, including a significant increase in LAMP1+ lysosomes, and the removal of lens organelles from the center of the lens. Specific inhibition of just the PI3K/Akt signaling axis was directly linked to the elimination of mitochondria and ER, while pan-PI3K inhibitors that block all PI3K downstream signaling removed all organelles, including nuclei. Therefore, blocking the PI3K/Akt pathway was alone insufficient to remove nuclei. RNAseq analysis revealed increased mRNA levels of the endogenous inhibitor of PI3K activation, PIK3IP1, in differentiating lens fiber cells preceding the induction of OFZ formation. Co-immunoprecipitation confirmed that PIK3IP1 associates with multiple PI3K p110 isoforms just prior to formation of the OFZ, providing a likely endogenous mechanism for blocking all PI3K signaling and activating the autophagy pathway required to form the OFZ during lens development.
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Affiliation(s)
- Rifah Gheyas
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Ramon Ortega-Alvarez
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Daniel Chauss
- Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | - Marc Kantorow
- Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | - A Sue Menko
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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Liao HY, Wang ZQ, Ran R, Zhou KS, Ma CW, Zhang HH. Biological Functions and Therapeutic Potential of Autophagy in Spinal Cord Injury. Front Cell Dev Biol 2022; 9:761273. [PMID: 34988074 PMCID: PMC8721099 DOI: 10.3389/fcell.2021.761273] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy is an evolutionarily conserved lysosomal degradation pathway that maintains metabolism and homeostasis by eliminating protein aggregates and damaged organelles. Many studies have reported that autophagy plays an important role in spinal cord injury (SCI). However, the spatiotemporal patterns of autophagy activation after traumatic SCI are contradictory. Most studies show that the activation of autophagy and inhibition of apoptosis have neuroprotective effects on traumatic SCI. However, reports demonstrate that autophagy is strongly associated with distal neuronal death and the impaired functional recovery following traumatic SCI. This article introduces SCI pathophysiology, the physiology and mechanism of autophagy, and our current review on its role in traumatic SCI. We also discuss the interaction between autophagy and apoptosis and the therapeutic effect of activating or inhibiting autophagy in promoting functional recovery. Thus, we aim to provide a theoretical basis for the biological therapy of SCI.
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Affiliation(s)
- Hai-Yang Liao
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Zhi-Qiang Wang
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Rui Ran
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Kai-Sheng Zhou
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Chun-Wei Ma
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Hai-Hong Zhang
- Lanzhou University Second Hospital, Lanzhou, China.,Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
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50
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Locatelli AG, Cenci S. Autophagy and longevity: Evolutionary hints from hyper-longevous mammals. Front Endocrinol (Lausanne) 2022; 13:1085522. [PMID: 36605941 PMCID: PMC9807614 DOI: 10.3389/fendo.2022.1085522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Abstract
Autophagy is a fundamental multi-tasking adaptive cellular degradation and recycling strategy. Following its causal implication in age-related decline, autophagy is currently among the most broadly studied and challenged mechanisms within aging research. Thanks to these efforts, new cellular nodes interconnected with this phylogenetically ancestral pathway and unexpected roles of autophagy-associated genetic products are unveiled daily, yet the history of functional adaptations of autophagy along its evolutive trail is poorly understood and documented. Autophagy is traditionally studied in canonical and research-wise convenient model organisms such as yeast and mice. However, unconventional animal models endowed with extended longevity and exemption from age-related diseases offer a privileged perspective to inquire into the role of autophagy in the evolution of longevity. In this mini review we retrace the appearance and functions evolved by autophagy in eukaryotic cells and its protective contribution in the pathophysiology of aging.
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Affiliation(s)
- Andrea G. Locatelli
- Age Related Diseases, San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milano, Italy
- *Correspondence: Andrea G. Locatelli, ; Simone Cenci,
| | - Simone Cenci
- Age Related Diseases, San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milano, Italy
- University Vita-Salute San Raffaele, Milano, Italy
- *Correspondence: Andrea G. Locatelli, ; Simone Cenci,
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