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Wang W, Wen Y, Luo J, Miao Y, Zhang F, Niu J. Heat shock transcription factor 2 reduces mitochondrial pathway apoptosis in intestinal epithelial cells by inhibiting the increase in mitochondrial membrane permeability in ulcerative colitis. PLoS One 2025; 20:e0325275. [PMID: 40440295 PMCID: PMC12121780 DOI: 10.1371/journal.pone.0325275] [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: 09/24/2024] [Accepted: 05/08/2025] [Indexed: 06/02/2025] Open
Abstract
The destruction of intestinal mucosal mechanical barrier homeostasis caused by excessive apoptosis of intestinal epithelial cells (IECs) is an important reason for the occurrence and development of ulcerative colitis (UC). The increase in mitochondrial membrane permeability caused by the opening of the mitochondrial membrane permeability transition pore (mPTP) is a key link in the initiation of mitochondrial pathway apoptosis. Our previous studies revealed that heat shock transcription factor 2 (HSF2), which is highly expressed in the intestinal mucosa of UC patients, can inhibit the expression of the cytochrome C (Cyto-C)/Caspase-9/Caspase-3 proteins in the mitochondrial pathway of apoptosis, but the regulatory mechanism is unknown. It has been reported that heat shock proteins regulated by heat shock transcription factors are closely related to mPTP opening. Therefore, we hypothesized that HSF2 affects mitochondrial pathway apoptosis in IECs by regulating mPTP opening. In this study, we altered the level of HSF2 in Caco-2 cells by lentivirus transfection to explore the changes in the mitochondrial membrane permeability of Caco-2 cells in an inflammatory environment. Subsequently, the mPTP agonist atractylorhizin (Atr) and inhibitor cyclosporine A (CsA) were used to clarify the regulatory effects of HSF2 on mPTP and the Cyto-C/Caspase-9/Caspase-3 pathways. Our study confirmed for the first time that HSF2 plays a protective role in UC by inhibiting mPTP opening, the increase in mitochondrial membrane permeability and the activation of the mitochondrial-mediated apoptosis pathway in IECs.
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Affiliation(s)
- Wen Wang
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, China
| | - Yunling Wen
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, China
| | - Juan Luo
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, China
| | - Yinglei Miao
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, China
| | - Fengrui Zhang
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, China
| | - Junkun Niu
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, China
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Chen X, An H, He J, Guo J, Xu S, Wu C, Wu D, Ji X. Mitochondrial unfolded protein response (UPR mt) as novel therapeutic targets for neurological disorders. J Cereb Blood Flow Metab 2025:271678X251341293. [PMID: 40370320 DOI: 10.1177/0271678x251341293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
Neurological disorders, including brain cancer, neurodegenerative diseases and ischemic/reperfusion injury, pose a significant threat to global human health. Due to the high metabolic demands of nerve cells, mitochondrial dysfunction is a critical feature of these disorders. The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response, which is critical for maintaining mitochondrial and energetic homeostasis under stress. Previous studies have found that UPRmt participates in diverse physiological processes especially metabolism and immunity. Currently, increasing evidence suggest that targeted regulation of UPRmt can also effectively delay the progression of neurological diseases and improve patients' prognosis. This review provides a comprehensive overview of UPRmt in the context of neurological diseases, with a particular emphasis on its regulatory functions. Additionally, we summarize the mechanistic insights into UPRmt in neurological disorders as investigated in preclinical studies, as well as its potential as a therapeutic target in the clinical management of neurological tumors. By highlighting the importance of UPRmt in the complex processes underlying neurological disorders, this review aims to bridge current knowledge gaps and inspire novel therapeutic strategies for these conditions.
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Affiliation(s)
- Xi Chen
- Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
| | - Hong An
- Department of Neurology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jiachen He
- Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
| | - Jiaqi Guo
- Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
| | - Shuaili Xu
- Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
| | - Chuanjie Wu
- Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
| | - Di Wu
- Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
| | - Xunming Ji
- Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
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Peng B, Wang Y, Zhang H. Mitonuclear Communication in Stem Cell Function. Cell Prolif 2025; 58:e13796. [PMID: 39726221 PMCID: PMC12099226 DOI: 10.1111/cpr.13796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 12/28/2024] Open
Abstract
Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan.
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Affiliation(s)
- Baozhou Peng
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Yaning Wang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Hongbo Zhang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
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Skrabalak I, Rajtak A, Malachowska B, Skrzypczak N, Skalina KA, Guha C, Kotarski J, Okla K. Therapy resistance: Modulating evolutionarily conserved heat shock protein machinery in cancer. Cancer Lett 2025; 616:217571. [PMID: 39986370 DOI: 10.1016/j.canlet.2025.217571] [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: 12/09/2024] [Revised: 02/16/2025] [Accepted: 02/17/2025] [Indexed: 02/24/2025]
Abstract
Therapy resistance is a major barrier to achieving a cure in cancer patients, often resulting in relapses and mortality. Heat shock proteins (HSPs) are a group of evolutionarily conserved proteins that play a prominent role in the progression of cancer and drug resistance. HSP synthesis is upregulated in cancer cells, facilitating adaptation to various tumor microenvironment (TME) stressors, including nutrient deprivation, exposure to DNA-damaging agents, hypoxia, and immune responses. In this review, we present background information about HSP-mediated cancer therapy resistance. Within this context, we emphasize recent progress in the understanding of HSP machinery, exploring the therapeutic potential of HSPs in cancer treatment.
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Affiliation(s)
- Ilona Skrabalak
- The First Department of Oncologic Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland
| | - Alicja Rajtak
- The First Department of Oncologic Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland; IOA, 3 Lotnicza St, 20-322 Lublin, Poland
| | - Beata Malachowska
- Department of Radiation Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Natalia Skrzypczak
- Department of Pathology and Clinical Laboratories, University of Michigan, Ann Arbor, MI, USA
| | - Karin A Skalina
- Department of Radiation Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Chandan Guha
- Department of Radiation Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Jan Kotarski
- The First Department of Oncologic Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland
| | - Karolina Okla
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; IOA, 3 Lotnicza St, 20-322 Lublin, Poland.
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Fiser O, Muller P. Role of HSF1 in cell division, tumorigenesis and therapy: a literature review. Cell Div 2025; 20:11. [PMID: 40287736 PMCID: PMC12034185 DOI: 10.1186/s13008-025-00153-1] [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: 12/22/2024] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
Heat shock factor 1 (HSF1) is the master orchestrator of the heat shock response (HSR), a critical process for maintaining cellular health and protein homeostasis. These effects are achieved through rapid expression of molecular chaperones, the heat shock proteins (HSPs), which ensure correct protein folding, repair, degradation and stabilization of multiprotein complexes. In addition to its role in the HSR, HSF1 influences the cell cycle, including processes such as S phase progression and regulation of the p53 pathway, highlighting its importance in cellular protein synthesis and division. While HSF1 activity offers neuroprotective benefits in neurodegenerative diseases, its proteome-stabilizing function may also reinforce tumorigenic transformation. HSF1 overexpression in many types of cancer reportedly enhances cell growth enables survival, alters metabolism, weakens immune response and promotes angiogenesis or epithelial-mesenchymal transition (EMT) as these cells enter a form of "HSF1 addiction". Furthermore, the client proteins of HSF1-regulated chaperones, particularly Hsp90, include numerous key players in classical tumorigenic pathways. HSF1 thus presents a promising therapeutic target for cancer treatment, potentially in combination with HSP inhibitors to alleviate typical initiation of HSR upon their use.
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Affiliation(s)
- Otakar Fiser
- Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Petr Muller
- Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic.
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Turkkol A, Kolac UK, Donmez Yalcin G, Bilgin MD, Yalcin A, Bilgen M. Enhancing Sonodynamic Therapy in Prostate Cancer: Cavitation-Induced Cytotoxicity and Mitochondrial Unfolded Protein Response Disruption. Cell Biochem Biophys 2025:10.1007/s12013-025-01717-2. [PMID: 40131613 DOI: 10.1007/s12013-025-01717-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/02/2025] [Indexed: 03/27/2025]
Abstract
Prostate cancer remains a significant health challenge, necessitating more effective and targeted treatment strategies. Sonodynamic therapy (SDT) is a promising, non-invasive approach that utilizes ultrasound-activated sensitizers to induce cancer cell death. However, the role of ultrasound cavitation in enhancing SDT efficacy and its effects on mitochondrial stress responses remain unclear. We hypothesized that increasing cavitation density through optimized ultrasound parameters would enhance Ce6-mediated SDT effectiveness by increasing cytotoxicity, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) loss, and disrupting the mitochondrial unfolded protein response (mtUPR). Prostate cancer cells were treated with Ce6 and exposed to ultrasound with varying duty cycles (50% and 100%) and power intensities (0.5 W/cm2, 1 W/cm2, and 1.5 W/cm2). Cavitation density was measured, and its effects on cell viability, ROS levels, MMP disruption, and mtUPR mediator expression, including activating transcription factor 5 (ATF5), heat shock protein 60 (HSP60), and caseinolytic protease proteolytic subunit (CLPP), were analyzed at protein and mRNA levels. Higher duty cycles significantly increased cavitation density, leading to enhanced cytotoxicity, elevated ROS generation, and greater MMP loss in Ce6-mediated SDT. Additionally, SDT reduced mtUPR mediator expression, with cavitation further amplifying these effects. These findings suggest that cavitation-enhanced SDT may contribute to improved therapeutic efficacy in prostate cancer treatment by modulating mitochondrial stress responses and affecting cell viability. Optimizing ultrasound parameters to maximize cavitation effects may contribute to the development of more effective SDT-based cancer therapies.
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Affiliation(s)
- Aysegul Turkkol
- Department of Biophysics, School of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
| | - Umut Kerem Kolac
- Department of Medical Biology, School of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
| | - Gizem Donmez Yalcin
- Department of Medical Biology, School of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
| | - Mehmet Dincer Bilgin
- Department of Biophysics, School of Medicine, Aydin Adnan Menderes University, Aydin, Turkey.
| | - Abdullah Yalcin
- Department of Medical Biology, School of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
| | - Mehmet Bilgen
- Department of Biophysics, School of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
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Gu J, He Y, He C, Zhang Q, Huang Q, Bai S, Wang R, You Q, Wang L. Advances in the structures, mechanisms and targeting of molecular chaperones. Signal Transduct Target Ther 2025; 10:84. [PMID: 40069202 PMCID: PMC11897415 DOI: 10.1038/s41392-025-02166-2] [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: 07/29/2024] [Revised: 11/25/2024] [Accepted: 01/15/2025] [Indexed: 03/15/2025] Open
Abstract
Molecular chaperones, a class of complex client regulatory systems, play significant roles in the prevention of protein misfolding and abnormal aggregation, the modulation of protein homeostasis, and the protection of cells from damage under constantly changing environmental conditions. As the understanding of the biological mechanisms of molecular chaperones has increased, their link with the occurrence and progression of disease has suggested that these proteins are promising targets for therapeutic intervention, drawing intensive interest. Here, we review recent advances in determining the structures of molecular chaperones and heat shock protein 90 (HSP90) chaperone system complexes. We also describe the features of molecular chaperones and shed light on the complicated regulatory mechanism that operates through interactions with various co-chaperones in molecular chaperone cycles. In addition, how molecular chaperones affect diseases by regulating pathogenic proteins has been thoroughly analyzed. Furthermore, we focus on molecular chaperones to systematically discuss recent clinical advances and various drug design strategies in the preclinical stage. Recent studies have identified a variety of novel regulatory strategies targeting molecular chaperone systems with compounds that act through different mechanisms from those of traditional inhibitors. Therefore, as more novel design strategies are developed, targeting molecular chaperones will significantly contribute to the discovery of new potential drugs.
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Affiliation(s)
- Jinying Gu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yanyi He
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chenxi He
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qiuyue Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qifei Huang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shangjun Bai
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ruoning Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Provincial TCM Engineering Technology Research Center of Highly Efficient Drug Delivery Systems (DDSs), Nanjing, China.
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Lei Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
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8
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Li X, Wang Z, Gao B, Dai K, Wu J, Shen K, Li G, Niu X, Wu X, Li L, Shen H, Li H, Yu Z, Wang Z, Chen G. Unveiling the impact of SUMOylation at K298 site of heat shock factor 1 on glioblastoma malignant progression. Neoplasia 2024; 57:101055. [PMID: 39260131 PMCID: PMC11415976 DOI: 10.1016/j.neo.2024.101055] [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: 07/04/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUND Glioblastoma (GBM) poses a significant medical challenge due to its aggressive nature and poor prognosis. Mitochondrial unfolded protein response (UPRmt) and the heat shock factor 1 (HSF1) pathway play crucial roles in GBM pathogenesis. Post-translational modifications, such as SUMOylation, regulate the mechanism of action of HSF1 and may influence the progression of GBM. Understanding the interplay between SUMOylation-modified HSF1 and GBM pathophysiology is essential for developing targeted therapies. METHODS We conducted a comprehensive investigation using cellular, molecular, and in vivo techniques. Cell culture experiments involved establishing stable cell lines, protein extraction, Western blotting, co-immunoprecipitation, and immunofluorescence analysis. Mass spectrometry was utilized for protein interaction studies. Computational modeling techniques were employed for protein structure analysis. Plasmid construction and lentiviral transfection facilitated the manipulation of HSF1 SUMOylation. In vivo studies employed xenograft models for tumor growth assessment. RESULTS Our research findings indicate that HSF1 primarily undergoes SUMOylation at the lysine residue K298, enhancing its nuclear translocation, stability, and downstream heat shock protein expression, while having no effect on its trimer conformation. SUMOylated HSF1 promoted the UPRmt pathway, leading to increased GBM cell proliferation, migration, invasion, and reduced apoptosis. In vivo studies have confirmed that SUMOylation of HSF1 enhances its oncogenic effect in promoting tumor growth in GBM xenograft models. CONCLUSION This study elucidates the significance of SUMOylation modification of HSF1 in driving GBM progression. Targeting SUMOylated HSF1 may offer a novel therapeutic approach for GBM treatment. Further investigation into the specific molecular mechanisms influenced by SUMOylated HSF1 is warranted for the development of effective targeted therapies to improve outcomes for GBM patients.
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Affiliation(s)
- Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China; Department of Neurosurgery, Xinghua People's Hospital Affiliated to Yangzhou University, Xinghua 225700, China
| | - Zongqi Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Bixi Gao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Kun Dai
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Jiang Wu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Kecheng Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Guangzhao Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Xiaowang Niu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Xin Wu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Longyuan Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Zhengquan Yu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
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Zhang Y, Pan R, Li K, Cheang LH, Zhao J, Zhong Z, Li S, Wang J, Zhang X, Cheng Y, Zheng X, He R, Wang H. HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling. Int J Biol Sci 2024; 20:5162-5190. [PMID: 39430254 PMCID: PMC11489178 DOI: 10.7150/ijbs.100015] [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: 06/24/2024] [Accepted: 09/13/2024] [Indexed: 10/22/2024] Open
Abstract
Malignant transformation is concomitant with excessive activation of stress response pathways. Heat shock proteins (HSPs) are stress-inducible proteins that play a role in folding and processing proteins, contributing to the non-oncogene addiction of stressed tumor cells. However, the detailed role of the HSP family in osteosarcoma has not been investigated. Bulk and single-cell transcriptomic data from the GEO and TARGET databases were used to identify HSPs associated with prognosis in osteosarcoma patients. The expression level of HSPD1 was markedly increased in osteosarcoma, correlating with a negative prognosis. Through in vitro and in vivo experiments, we systematically identified HSPD1 as an important contributor to the regulation of proliferation, metastasis, and apoptosis in osteosarcoma by promoting the epithelial-mesenchymal transition (EMT) and activating AKT/mTOR signaling. Subsequently, ATP5A1 was determined as a potential target of HSPD1 using immunoprecipitation followed by mass spectrometry. Mechanistically, HSPD1 may interact with ATP5A1 to reduce the K48-linked ubiquitination and degradation of ATP5A1, which ultimately activates the AKT/mTOR pathway to ensure osteosarcoma progression and EMT process. These findings expand the potential mechanisms by which HSPD1 exerts biological effects and provide strong evidence for its inclusion as a potential therapeutic target in osteosarcoma.
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Affiliation(s)
- Yiming Zhang
- Department of Sports Medicine, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Speed Capability, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Ruilin Pan
- Department of Sports Medicine, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Speed Capability, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Kun Li
- Department of Sports Medicine, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Speed Capability, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Drug Ability Assessment, Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of the Chinese Ministry of Education, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, China
| | - Lek Hang Cheang
- Department of Orthopedic Surgery, Centro Hospitalar Conde de Sao Januario, Macau, China
| | - Jing Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, China
| | - Zhangfeng Zhong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, China
| | - Shaoping Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, China
| | - Jinghao Wang
- Department of Pharmacy, the First Affiliated Hospital, State Key Laboratory of Frigid Zone Cardiovascular Diseases, Jinan University, Guangzhou, China
- Department of Orthopedics, NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaofang Zhang
- Department of Pharmacy, the First Affiliated Hospital, State Key Laboratory of Frigid Zone Cardiovascular Diseases, Jinan University, Guangzhou, China
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150086, Heilongjiang, China
| | - Yanmei Cheng
- Department of Cardiothoracic Surgery ICU, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Xiaofei Zheng
- Department of Sports Medicine, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Speed Capability, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Rongrong He
- State Key Laboratory of Bioactive Molecules and Drug Ability Assessment, Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of the Chinese Ministry of Education, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, China
| | - Huajun Wang
- Department of Sports Medicine, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Speed Capability, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, Jinan University, Guangzhou, China
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10
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Torres AK, Fleischhart V, Inestrosa NC. Mitochondrial unfolded protein response (UPR mt): what we know thus far. Front Cell Dev Biol 2024; 12:1405393. [PMID: 38882057 PMCID: PMC11176431 DOI: 10.3389/fcell.2024.1405393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 05/06/2024] [Indexed: 06/18/2024] Open
Abstract
Mitochondria are key organelles for the optimal function of the cell. Among their many functions, they maintain protein homeostasis through their own proteostatic machinery, which involves proteases and chaperones that regulate protein import and folding inside mitochondria. In the early 2000s, the mitochondrial unfolded protein response (UPRmt) was first described in mammalian cells. This stress response is activated by the accumulation of unfolded/misfolded proteins within the mitochondrial matrix, which results in the transmission of a signal to the nucleus to increase the expression of proteases and chaperones to address the abnormal mitochondrial protein load. After its discovery, this retrograde signaling pathway has also been described in other organisms of different complexities, suggesting that it is a conserved stress response. Although there are some specific differences among organisms, the mechanism of this stress response is mostly similar and involves the transmission of a signal from mitochondria to the nucleus that induces chromatin remodeling to allow the binding of specific transcription factors to the promoters of chaperones and proteases. In the last decade, proteins and signaling pathways that could be involved in the regulation of the UPRmt, including the Wnt signaling pathway, have been described. This minireview aims to summarize what is known about the mechanism of the UPRmt and its regulation, specifically in mammals and C. elegans.
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Affiliation(s)
- Angie K Torres
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile
| | - Veronika Fleischhart
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile
| | - Nibaldo C Inestrosa
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile
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11
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Tausif YM, Thekkekkara D, Sai TE, Jahagirdar V, Arjun HR, Meheronnisha SK, Babu A, Banerjee A. Heat shock protein paradigms in cancer progression: future therapeutic perspectives. 3 Biotech 2024; 14:96. [PMID: 38449709 PMCID: PMC10912419 DOI: 10.1007/s13205-024-03951-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 01/28/2024] [Indexed: 03/08/2024] Open
Abstract
Heat-shock proteins (HSPs), also known as stress proteins, are ubiquitously present in all forms of life. They play pivotal roles in protein folding and unfolding, the formation of multiprotein complexes, the transportation and sorting of proteins into their designated subcellular compartments, the regulation of the cell cycle, and signalling processes. These HSPs encompass HSP27, HSP40, HSP70, HSP60, and HSP90, each contributing to various cellular functions. In the context of cancer, HSPs exert influence by either inhibiting or activating diverse signalling pathways, thereby impacting growth, differentiation, and cell division. This article offers an extensive exploration of the functions of HSPs within the realms of pharmacology and cancer biology. HSPs are believed to play substantial roles in the mechanisms underlying the initiation and progression of cancer. They hold promise as valuable clinical markers for cancer diagnosis, potential targets for therapeutic interventions, and indicators of disease progression. In times of cellular stress, HSPs function as molecular chaperones, safeguarding the structural and functional integrity of proteins and aiding in their proper folding. Moreover, HSPs play a crucial role in cancer growth, by regulating processes such as angiogenesis, cell proliferation, migration, invasion, and metastasis.
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Affiliation(s)
- Y. Mohammed Tausif
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570 015 India
| | - Dithu Thekkekkara
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570 015 India
| | - Thummuru Ekshita Sai
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570 015 India
| | - Vaishnavi Jahagirdar
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570 015 India
| | - H. R. Arjun
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570 015 India
| | - S. K. Meheronnisha
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570 015 India
| | - Amrita Babu
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570 015 India
| | - Aniruddha Banerjee
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570 015 India
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Paul R, Shreya S, Pandey S, Shriya S, Abou Hammoud A, Grosset CF, Prakash Jain B. Functions and Therapeutic Use of Heat Shock Proteins in Hepatocellular Carcinoma. LIVERS 2024; 4:142-163. [DOI: 10.3390/livers4010011] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/10/2024] Open
Abstract
Heat shock proteins are intracellular proteins expressed in prokaryotes and eukaryotes that help protect the cell from stress. They play an important role in regulating cell cycle and cell death, work as molecular chaperons during the folding of newly synthesized proteins, and also in the degradation of misfolded proteins. They are not only produced under stress conditions like acidosis, energy depletion, and oxidative stress but are also continuously synthesized as a result of their housekeeping functions. There are different heat shock protein families based on their molecular weight, like HSP70, HSP90, HSP60, HSP27, HSP40, etc. Heat shock proteins are involved in many cancers, particularly hepatocellular carcinoma, the main primary tumor of the liver in adults. Their deregulations in hepatocellular carcinoma are associated with metastasis, angiogenesis, cell invasion, and cell proliferation and upregulated heat shock proteins can be used as either diagnostic or prognostic markers. Targeting heat shock proteins is a relevant strategy for the treatment of patients with liver cancer. In this review, we provide insights into heat shock proteins and heat shock protein-like proteins (clusterin) in the progression of hepatocellular carcinoma and their use as therapeutic targets.
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Affiliation(s)
- Ramakrushna Paul
- Gene Expression and Signaling Lab, Department of Zoology, Mahatma Gandhi Central University, Motihari 845401, India
| | - Smriti Shreya
- Gene Expression and Signaling Lab, Department of Zoology, Mahatma Gandhi Central University, Motihari 845401, India
| | | | - Srishti Shriya
- Gene Expression and Signaling Lab, Department of Zoology, Mahatma Gandhi Central University, Motihari 845401, India
| | - Aya Abou Hammoud
- MIRCADE Team, U1312, Bordeaux Institute of Oncology, BRIC, INSERM, University of Bordeaux, 33000 Bordeaux, France
| | - Christophe F. Grosset
- MIRCADE Team, U1312, Bordeaux Institute of Oncology, BRIC, INSERM, University of Bordeaux, 33000 Bordeaux, France
| | - Buddhi Prakash Jain
- Gene Expression and Signaling Lab, Department of Zoology, Mahatma Gandhi Central University, Motihari 845401, India
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13
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Gao B, Wang Z, Dai K, Wang Y, Li L, Li G, Niu X, Li X, Yu Z, Wang Z, Chen G. Acetylation of mtHSP70 at Lys595/653 affecting its interaction between GrpEL1 regulates glioblastoma progression via UPRmt. Free Radic Biol Med 2024; 213:394-408. [PMID: 38281626 DOI: 10.1016/j.freeradbiomed.2024.01.035] [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: 10/14/2023] [Revised: 01/01/2024] [Accepted: 01/21/2024] [Indexed: 01/30/2024]
Abstract
BACKGROUND The mitochondrial unfolded protein response (UPRmt) is a vital biological process that regulates mitochondrial protein homeostasis and enables glioblastoma cells to cope with mitochondrial oxidative stress in the tumor microenvironment. We previously reported that the binding of mitochondrial stress-70 protein (mtHSP70) to GrpE protein homolog 1 (GrpEL1) is involved in the regulation of the UPRmt. However, the mechanisms regulating their binding remain unclear. Herein, we examined the UPRmt in glioblastoma and explored whether modulating the interaction between mtHSP70 and GrpEL1 affects the UPRmt. METHODS Western blot analysis, aggresome staining, and transmission electron microscopy were used to detect the activation of the UPRmt and protein aggregates within mitochondria. Molecular dynamics simulations were performed to investigate the impact of different mutations in mtHSP70 on its binding to GrpEL1. Endogenous site-specific mutations were introduced into mtHSP70 in glioblastoma cells using CRISPR/Cas9. In vitro and in vivo experiments were conducted to assess mitochondrial function and glioblastoma progression. RESULTS The UPRmt was activated in glioblastoma cells in response to oxidative stress. mtHSP70 regulated mitochondrial protein homeostasis by facilitating UPRmt-progress protein import into the mitochondria. Acetylation of mtHSP70 at Lys595/653 enhanced its binding to GrpEL1. Missense mutations at Lys595/653 increased mitochondrial protein aggregates and inhibited glioblastoma progression in vitro and in vivo. CONCLUSIONS We identified an innovative mechanism in glioblastoma progression by which acetylation of mtHSP70 at Lys595/653 influences its interaction with GrpEL1 to regulate the UPRmt. Mutations at Lys595/653 in mtHSP70 could potentially serve as therapeutic targets and prognostic indicators of glioblastoma.
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Affiliation(s)
- Bixi Gao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Zongqi Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Kun Dai
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Yunjiang Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China; Department of Neurosurgery, Yancheng Third People's Hospital, Yancheng, 224000, China
| | - Longyuan Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Guangzhao Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China; Department of Neurosurgery, Hefei First People's Hospital, Hefei, 230031, China
| | - Xiaowang Niu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China; Department of Neurosurgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, China
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China; Department of Neurosurgery, Xinghua People's Hospital, Xinghua, 225700, China
| | - Zhengquan Yu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China.
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
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14
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Somu P, Mohanty S, Basavegowda N, Yadav AK, Paul S, Baek KH. The Interplay between Heat Shock Proteins and Cancer Pathogenesis: A Novel Strategy for Cancer Therapeutics. Cancers (Basel) 2024; 16:638. [PMID: 38339390 PMCID: PMC10854888 DOI: 10.3390/cancers16030638] [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: 01/15/2024] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
Heat shock proteins (HSPs) are developmentally conserved families of protein found in both prokaryotic and eukaryotic organisms. HSPs are engaged in a diverse range of physiological processes, including molecular chaperone activity to assist the initial protein folding or promote the unfolding and refolding of misfolded intermediates to acquire the normal or native conformation and its translocation and prevent protein aggregation as well as in immunity, apoptosis, and autophagy. These molecular chaperonins are classified into various families according to their molecular size or weight, encompassing small HSPs (e.g., HSP10 and HSP27), HSP40, HSP60, HSP70, HSP90, and the category of large HSPs that include HSP100 and ClpB proteins. The overexpression of HSPs is induced to counteract cell stress at elevated levels in a variety of solid tumors, including anticancer chemotherapy, and is closely related to a worse prognosis and therapeutic resistance to cancer cells. HSPs are also involved in anti-apoptotic properties and are associated with processes of cancer progression and development, such as metastasis, invasion, and cell proliferation. This review outlines the previously mentioned HSPs and their significant involvement in diverse mechanisms of tumor advancement and metastasis, as well as their contribution to identifying potential targets for therapeutic interventions.
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Affiliation(s)
- Prathap Somu
- Department of Biotechnology and Chemical Engineering, School of Civil & Chemical Engineering, Manipal University Jaipur, Dehmi Kalan, Jaipur 303007, India;
| | - Sonali Mohanty
- Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela 769008, India;
| | - Nagaraj Basavegowda
- Department of Biotechnology, Yeungnam University, Gyeongsan 38451, Republic of Korea;
| | - Akhilesh Kumar Yadav
- Department of Environmental Engineering and Management, Chaoyang University of Technology, Taichung 413310, Taiwan;
- Department of Bioengineering, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Chennai 602105, India
| | - Subhankar Paul
- Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela 769008, India;
| | - Kwang-Hyun Baek
- Department of Biotechnology, Yeungnam University, Gyeongsan 38451, Republic of Korea;
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15
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Zhang M, Bi X. Heat Shock Proteins and Breast Cancer. Int J Mol Sci 2024; 25:876. [PMID: 38255948 PMCID: PMC10815085 DOI: 10.3390/ijms25020876] [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: 11/15/2023] [Revised: 01/01/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Heat shock proteins (Hsps) are a group of stress-induced proteins involved in protein folding and maturation. Based on their molecular weight, Hsps can be divided into six families: small Hsps, Hsp40, Hsp60, Hsp70, Hsp90, and large Hsps. In the process of breast cancer tumorigenesis, Hsps play a central role in regulating cell reactions and functions including proliferation, metastasis, and apoptosis. Moreover, some of the critical Hsps also regulate the fine balance between the protective and destructive immunological responses within the tumor microenvironment. In this review, we systematically summarize the roles of major Hsps in breast cancer biology and point out the potential uses of these proteins in breast cancer diagnosis and therapy. Understanding the roles of different families of Hsps in breast cancer pathogenesis will help in the development of more effective prevention and treatment measures for breast cancer.
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Affiliation(s)
- Miao Zhang
- Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
- Institute of Microbiology, Jiangxi Academy of Sciences, Nanchang 330096, China
| | - Xiaowen Bi
- Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
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Chattopadhyay M, Chanda A, Pal B. Unravelling the Nexus: Mitochondrial Oxidative Stress, Tumour Microenvironment, and Escape from Immune Surveillance. CANCER DRUG DISCOVERY AND DEVELOPMENT 2024:255-286. [DOI: 10.1007/978-3-031-66421-2_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
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17
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Gambardella J, Santulli G, Fiordelisi A, Cerasuolo FA, Wang X, Prevete N, Sommella E, Avvisato R, Buonaiuto A, Altobelli GG, Rinaldi L, Chiuso F, Feliciello A, Dal Piaz F, Campiglia P, Ciccarelli M, Morisco C, Sadoshima J, Iaccarino G, Sorriento D. Infiltrating macrophages amplify doxorubicin-induced cardiac damage: role of catecholamines. Cell Mol Life Sci 2023; 80:323. [PMID: 37819449 PMCID: PMC10567889 DOI: 10.1007/s00018-023-04922-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 08/12/2023] [Accepted: 08/13/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND The functional contribution of non-myocyte cardiac cells, such as inflammatory cells, in the setup of heart failure in response to doxorubicin (Dox) is recently becoming of growing interest. OBJECTIVES The study aims to evaluate the role of macrophages in cardiac damage elicited by Dox treatment. METHODS C57BL/6 mice were treated with one intraperitoneal injection of Dox (20 mg/kg) and followed up for 5 days by cardiac ultrasounds (CUS), histological, and flow cytometry evaluations. We also tested the impact of Dox in macrophage-depleted mice. Rat cardiomyoblasts were directly treated with Dox (D-Dox) or with a conditioned medium from cultured murine macrophages treated with Dox (M-Dox). RESULTS In response to Dox, macrophage infiltration preceded cardiac damage. Macrophage depletion prevents Dox-induced damage, suggesting a key role of these cells in promoting cardiotoxicity. To evaluate the crosstalk between macrophages and cardiac cells in response to DOX, we compared the effects of D-Dox and M-Dox in vitro. Cell vitality was lower in cardiomyoblasts and apoptosis was higher in response to M-Dox compared with D-Dox. These events were linked to p53-induced mitochondria morphology, function, and autophagy alterations. We identify a mechanistic role of catecholamines released by Dox-activated macrophages that lead to mitochondrial apoptosis of cardiac cells through β-AR stimulation. CONCLUSIONS Our data indicate that crosstalk between macrophages and cardiac cells participates in cardiac damage in response to Dox.
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Affiliation(s)
- Jessica Gambardella
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Department of Medicine (Cardiology) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Montefiore University Hospital, New York, USA
| | - Gaetano Santulli
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Department of Medicine (Cardiology) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Montefiore University Hospital, New York, USA
- Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy
| | - Antonella Fiordelisi
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | | | - Xujun Wang
- Department of Medicine (Cardiology) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Montefiore University Hospital, New York, USA
| | - Nella Prevete
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), CNR, Naples, Italy
| | - Eduardo Sommella
- Department of Pharmacy, University of Salerno, Fisciano (Salerno), Italy
| | - Roberta Avvisato
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Antonietta Buonaiuto
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | | | - Laura Rinaldi
- Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy
| | - Francesco Chiuso
- Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy
| | - Antonio Feliciello
- Department of Molecular Medicine and Medical Biotechnology, Federico II University, Naples, Italy
| | - Fabrizio Dal Piaz
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno (Salerno), Baronissi, Italy
| | - Pietro Campiglia
- Department of Pharmacy, University of Salerno, Fisciano (Salerno), Italy
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno (Salerno), Baronissi, Italy
| | - Carmine Morisco
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
| | - Guido Iaccarino
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
- Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy
| | - Daniela Sorriento
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
- Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy.
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Wang Y, Abazid A, Badendieck S, Mustea A, Stope MB. Impact of Non-Invasive Physical Plasma on Heat Shock Protein Functionality in Eukaryotic Cells. Biomedicines 2023; 11:biomedicines11051471. [PMID: 37239142 DOI: 10.3390/biomedicines11051471] [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: 04/04/2023] [Revised: 05/06/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Recently, biomedical research has increasingly investigated physical plasma as an innovative therapeutic approach with a number of therapeutic biomedical effects. It is known from radiation and chemotherapy that these applications can lead to the induction and activation of primarily cytoprotective heat shock proteins (HSP). HSP protect cells and tissues from physical, (bio)chemical, and physiological stress and, ultimately, along with other mechanisms, govern resistance and treatment failure. These mechanisms are well known and comparatively well studied in drug therapy. For therapies in the field of physical plasma medicine, however, extremely little data are available to date. In this review article, we provide an overview of the current studies on the interaction of physical plasma with the cellular HSP system.
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Affiliation(s)
- Yanqing Wang
- Department of Gynecology and Gynecological Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Alexander Abazid
- Department of General, Visceral and Thorax Surgery, Bundeswehr Hospital Berlin, Scharnhorststrasse 13, 10115 Berlin, Germany
| | - Steffen Badendieck
- Department of General, Visceral and Thorax Surgery, Bundeswehr Hospital Berlin, Scharnhorststrasse 13, 10115 Berlin, Germany
| | - Alexander Mustea
- Department of Gynecology and Gynecological Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Matthias B Stope
- Department of Gynecology and Gynecological Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
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19
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Yang X, Zhu R, Song Z, Shi D, Huang J. Diversity in Cell Morphology, Composition, and Function among Adipose Depots in River Buffaloes. Int J Mol Sci 2023; 24:ijms24098410. [PMID: 37176117 PMCID: PMC10179058 DOI: 10.3390/ijms24098410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/01/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Fat deposition is a significant economic trait in livestock animals. Adipose tissues (ATs) developed in subcutaneous and visceral depots are considered waste whereas those within muscle are highly valued. In river buffaloes, lipogenesis is highly active in subcutaneous (especially in the sternum subcutaneous) and visceral depots but not in muscle tissue. Revealing the features and functions of ATs in different depots is significant for the regulation of their development. Here, we characterize the cell size, composition, and function of six AT depots in river buffaloes. Our data support that the subcutaneous AT depots have a larger cell size than visceral AT depots, and the subcutaneous AT depots, especially the sternum subcutaneous AT, are mainly associated with the extracellular matrix whereas the visceral AT depots are mainly associated with immunity. We found that sternum subcutaneous AT is significantly different from ATs in other depots, due to the high unsaturated fatty acid content and the significant association with metabolic protection. The perirenal AT is more active in FA oxidation for energy supply. In addition, the expression of HOX paralogs supports the variable origins of ATs in different depots, indicating that the development of ATs in different depots is mediated by their progenitor cells. The present study enhances our understanding of the cellular and molecular features, metabolism, and origin of AT depots in buffaloes, which is significant for the regulation of fat deposition and provides new insights into the features of AT depots in multiple discrete locations.
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Affiliation(s)
- Xintong Yang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning 530005, China
| | - Ruirui Zhu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning 530005, China
| | - Ziyi Song
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning 530005, China
| | - Deshun Shi
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning 530005, China
| | - Jieping Huang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning 530005, China
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20
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Duan Y, Yu J, Chen M, Lu Q, Ning F, Gan X, Liu H, Ye Y, Lu S, Lash GE. Knockdown of heat shock protein family D member 1 (HSPD1) promotes proliferation and migration of ovarian cancer cells via disrupting the stability of mitochondrial 3-oxoacyl-ACP synthase (OXSM). J Ovarian Res 2023; 16:81. [PMID: 37087461 PMCID: PMC10122320 DOI: 10.1186/s13048-023-01156-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 04/06/2023] [Indexed: 04/24/2023] Open
Abstract
BACKGROUND Heat shock protein 60 (HSP60) is essential for the folding and assembly of newly imported proteins to the mitochondria. HSP60 is overexpressed in most types of cancer, but its association with ovarian cancer is still in dispute. SKOV3 and OVCAR3 were used as experimental models after comparing the expression level of mitochondrial HSP60 in a normal human ovarian epithelial cell line and four ovarian cancer cell lines. RESULTS Low HSPD1 (Heat Shock Protein Family D (HSP60) Member 1) expression was associated with unfavorable prognosis in ovarian cancer patients. Knockdown of HSPD1 significantly promoted the proliferation and migration of ovarian cancer cells. The differentially expressed proteins after HSPD1 knockdown were enriched in the lipoic acid (LA) biosynthesis and metabolism pathway, in which mitochondrial 3-oxoacyl-ACP synthase (OXSM) was the most downregulated protein and responsible for lipoic acid synthesis. HSP60 interacted with OXSM and overexpression of OXSM or LA treatment could reverse proliferation promotion mediated by HSPD1 knockdown. CONCLUSIONS HSP60 interacted with OXSM and maintained its stability. Knockdown of HSPD1 could promote the proliferation and migration of SKOV3 and OVCAR3 via lowering the protein level of OXSM and LA synthesis.
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Affiliation(s)
- Yaoyun Duan
- Division of Uterine Vascular Biology, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Juan Yu
- Division of Uterine Vascular Biology, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Miaojuan Chen
- Division of Uterine Vascular Biology, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Qinsheng Lu
- Division of Uterine Vascular Biology, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Fen Ning
- Division of Uterine Vascular Biology, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Xiaowen Gan
- Division of Uterine Vascular Biology, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Hanbo Liu
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Yixin Ye
- Division of Uterine Vascular Biology, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Shenjiao Lu
- Division of Uterine Vascular Biology, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China
| | - Gendie E Lash
- Division of Uterine Vascular Biology, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China.
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21
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Czegle I, Huang C, Soria PG, Purkiss DW, Shields A, Wappler-Guzzetta EA. The Role of Genetic Mutations in Mitochondrial-Driven Cancer Growth in Selected Tumors: Breast and Gynecological Malignancies. Life (Basel) 2023; 13:996. [PMID: 37109525 PMCID: PMC10145875 DOI: 10.3390/life13040996] [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: 12/28/2022] [Revised: 03/15/2023] [Accepted: 03/31/2023] [Indexed: 04/29/2023] Open
Abstract
There is an increasing understanding of the molecular and cytogenetic background of various tumors that helps us better conceptualize the pathogenesis of specific diseases. Additionally, in many cases, these molecular and cytogenetic alterations have diagnostic, prognostic, and/or therapeutic applications that are heavily used in clinical practice. Given that there is always room for improvement in cancer treatments and in cancer patient management, it is important to discover new therapeutic targets for affected individuals. In this review, we discuss mitochondrial changes in breast and gynecological (endometrial and ovarian) cancers. In addition, we review how the frequently altered genes in these diseases (BRCA1/2, HER2, PTEN, PIK3CA, CTNNB1, RAS, CTNNB1, FGFR, TP53, ARID1A, and TERT) affect the mitochondria, highlighting the possible associated individual therapeutic targets. With this approach, drugs targeting mitochondrial glucose or fatty acid metabolism, reactive oxygen species production, mitochondrial biogenesis, mtDNA transcription, mitophagy, or cell death pathways could provide further tailored treatment.
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Affiliation(s)
- Ibolya Czegle
- Department of Internal Medicine and Haematology, Semmelweis University, H-1085 Budapest, Hungary
| | - Chelsea Huang
- Department of Pathology and Laboratory Medicine, Loma Linda University Health, Loma Linda, CA 92354, USA
| | - Priscilla Geraldine Soria
- Department of Pathology and Laboratory Medicine, Loma Linda University Health, Loma Linda, CA 92354, USA
| | - Dylan Wesley Purkiss
- Department of Pathology and Laboratory Medicine, Loma Linda University Health, Loma Linda, CA 92354, USA
| | - Andrea Shields
- Department of Pathology and Laboratory Medicine, Loma Linda University Health, Loma Linda, CA 92354, USA
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22
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Önay Uçar E, Şengelen A, Mertoğlu Kamalı E. Hsp27, Hsp60, Hsp70, or Hsp90 depletion enhances the antitumor effects of resveratrol via oxidative and ER stress response in human glioblastoma cells. Biochem Pharmacol 2023; 208:115409. [PMID: 36603687 DOI: 10.1016/j.bcp.2022.115409] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 12/22/2022] [Accepted: 12/29/2022] [Indexed: 01/03/2023]
Abstract
Therapeutic resistance of gliomas is still a crucial issue and closely related to induced heat shock response (HSR). Resveratrol (RSV) is a promising experimental agent for glioblastoma (GB) therapy. However, the role of heat shock protein (Hsp)27, Hsp60, Hsp70, and Hsp90 on the therapeutic efficacy of RSV remains unclear in gliomas. Herein, small interfering (si)RNA transfection was performed to block Hsp expressions. RSV treatments reduced glioma cells' viability dose- and time-dependent while keeping HEK-293 normal cells alive. Furthermore, a low dose of RSV (15 µM/48 h) offered protection against oxidative stress and apoptosis due to Hsp depletion in healthy cells. On the contrary, in glioma cells, RSV (15 µM/48 h) increased ROS (reactive oxygen species) production, led to autophagy and induced endoplasmic reticulum (ER) stress and apoptosis, and reduced 2D- and 3D-clonogenic survival. Hsp27, Hsp60, Hsp70, or Hsp90 depletion also resulted in cell death through ER stress response and ROS burst. Remarkably, the heat shock response (increased HSF1 levels) due to Hsp depletion was attenuated by RSV in glioma cells. Collectively, our data show that these Hsp silencings make glioma cells more sensitive to RSV treatment, indicating that these Hsps are potential therapeutic targets for GB treatment.
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Affiliation(s)
- Evren Önay Uçar
- Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Istanbul, Turkey.
| | - Aslıhan Şengelen
- Department of Molecular Biology and Genetics, Institute of Graduate Studies in Sciences, Istanbul University, Istanbul, Turkey.
| | - Elif Mertoğlu Kamalı
- Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Istanbul, Turkey.
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23
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Chitre S, Ray AM, Stevens M, Doud EH, Liechty H, Washburn A, Tepper K, Sivinski J, O'Hagan HM, Georgiadis MM, Chapman E, Johnson SM. Bis-aryl-α,β-unsaturated ketone (ABK) chaperonin inhibitors exhibit selective cytotoxicity to colorectal cancer cells that correlates with levels of aberrant HSP60 in the cytosol. Bioorg Med Chem 2022; 75:117072. [PMID: 36356534 PMCID: PMC11813185 DOI: 10.1016/j.bmc.2022.117072] [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: 08/29/2022] [Revised: 10/13/2022] [Accepted: 10/25/2022] [Indexed: 11/02/2022]
Abstract
While many studies have established the importance of protein homeostasis in tumor progression, little effort has been made to examine the therapeutic potential of targeting the HSP60 chaperonin system. In healthy cells, HSP60 is localized to the mitochondrial matrix; however, emerging evidence indicates HSP60 can be over-expressed and mis-localized to the cytosol of cancer cells, which is hypothesized to promote tumor cell survival and proliferation. This opens a potential avenue to selectively target the aberrant HSP60 in the cytosol as a chemotherapeutic strategy. In the present work, we examined a series of bis-aryl-α,β-unsaturated ketone (ABK) HSP60 inhibitors for their ability to selectively target cancerous vs non-cancerous colon and intestine cells. We found that lead analogs inhibited migration and clonogenicity of cancer cells, with cytotoxicity correlating with the level of aberrant HSP60 in the cytosol.
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Affiliation(s)
- Siddhi Chitre
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Anne-Marie Ray
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Mckayla Stevens
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Emma H Doud
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Hope Liechty
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Alex Washburn
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Katelyn Tepper
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Jared Sivinski
- The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., PO Box 210207, Tucson, AZ 85721, United States
| | - Heather M O'Hagan
- Indiana University School of Medicine, Medical Sciences Program and Department of Medical and Molecular Genetics, 1001 East 3rd St., Bloomington, IN 47405, United States
| | - Millie M Georgiadis
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Eli Chapman
- The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., PO Box 210207, Tucson, AZ 85721, United States
| | - Steven M Johnson
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
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24
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Parma B, Wurdak H, Ceppi P. Harnessing mitochondrial metabolism and drug resistance in non-small cell lung cancer and beyond by blocking heat-shock proteins. Drug Resist Updat 2022; 65:100888. [DOI: 10.1016/j.drup.2022.100888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/10/2022] [Accepted: 10/25/2022] [Indexed: 11/30/2022]
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25
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Inigo JR, Chandra D. The mitochondrial unfolded protein response (UPR mt): shielding against toxicity to mitochondria in cancer. J Hematol Oncol 2022; 15:98. [PMID: 35864539 PMCID: PMC9306209 DOI: 10.1186/s13045-022-01317-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 07/11/2022] [Indexed: 12/20/2022] Open
Abstract
Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt.
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Affiliation(s)
- Joseph R Inigo
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Dhyan Chandra
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
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26
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Zhang L, Liu Y, Zhou R, He B, Wang W, Zhang B. Cyclophilin D: Guardian or Executioner for Tumor Cells? Front Oncol 2022; 12:939588. [PMID: 35860554 PMCID: PMC9289278 DOI: 10.3389/fonc.2022.939588] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/09/2022] [Indexed: 11/13/2022] Open
Abstract
Cyclophilin D (CypD) is a peptide-proline cis-trans isomerase (PPIase) distributed in the mitochondrial matrix. CypD regulates the opening of the mitochondrial permeability conversion pore (mPTP) and mitochondrial bioenergetics through PPIase activity or interaction with multiple binding partners in mitochondria. CypD initially attracted attention due to its regulation of mPTP overopening-mediated cell death. However, recent studies on the effects of CypD on tumors have shown conflicting results. Although CypD has been proven to promote the aerobic glycolysis in tumor cells, its regulation of malignant characteristics such as the survival, invasion and drug resistance of tumor cells remains controversial. Here, we elaborate the main biological functions of CypD and its relationships with tumor progression identified in recent years, focusing on the dual role of CypD in tumors.
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Affiliation(s)
- Ling Zhang
- School of Nursing, Jining Medical University, Jining, China
- *Correspondence: Bin Zhang, ; Ling Zhang,
| | - Yi Liu
- School of Nursing, Jining Medical University, Jining, China
- School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Rou Zhou
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Baoyu He
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Wenjun Wang
- School of Nursing, Jining Medical University, Jining, China
| | - Bin Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
- Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Jining, China
- *Correspondence: Bin Zhang, ; Ling Zhang,
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27
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Wengert LA, Backe SJ, Bourboulia D, Mollapour M, Woodford MR. TRAP1 Chaperones the Metabolic Switch in Cancer. Biomolecules 2022; 12:biom12060786. [PMID: 35740911 PMCID: PMC9221471 DOI: 10.3390/biom12060786] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/02/2022] [Accepted: 06/02/2022] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in response to stress. The Hsp90 chaperone TNF-receptor-associated protein-1 (TRAP1) is primarily localized to the mitochondria and controls both cellular metabolic reprogramming and mitochondrial apoptosis. TRAP1 upregulation facilitates the growth and progression of many cancers by promoting glycolytic metabolism and antagonizing the mitochondrial permeability transition that precedes multiple cell death pathways. TRAP1 attenuation induces apoptosis in cellular models of cancer, identifying TRAP1 as a potential therapeutic target in cancer. Similar to cytosolic Hsp90 proteins, TRAP1 is also subject to post-translational modifications (PTM) that regulate its function and mediate its impact on downstream effectors, or ‘clients’. However, few effectors have been identified to date. Here, we will discuss the consequence of TRAP1 deregulation in cancer and the impact of post-translational modification on the known functions of TRAP1.
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Affiliation(s)
- Laura A. Wengert
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; (L.A.W.); (S.J.B.); (D.B.); (M.M.)
- Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Sarah J. Backe
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; (L.A.W.); (S.J.B.); (D.B.); (M.M.)
- Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Dimitra Bourboulia
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; (L.A.W.); (S.J.B.); (D.B.); (M.M.)
- Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Mehdi Mollapour
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; (L.A.W.); (S.J.B.); (D.B.); (M.M.)
- Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Mark R. Woodford
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; (L.A.W.); (S.J.B.); (D.B.); (M.M.)
- Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Correspondence:
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28
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Lu S, Wang R, Fu W, Si Y. Applications of Extracellular Vesicles in Abdominal Aortic Aneurysm. Front Cardiovasc Med 2022; 9:927542. [PMID: 35711380 PMCID: PMC9194528 DOI: 10.3389/fcvm.2022.927542] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 05/12/2022] [Indexed: 11/17/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) is a localized expansion of the abdominal aorta which can lead to lethal complication as the rupture of aortic wall. Currently there is still neither competent method to predict the impending rupture of aneurysm, nor effective treatment to arrest the progression of small and asymptomatic aneurysms. Accumulating evidence has confirmed the crucial role of extracellular vesicles (EVs) in the pathological course of AAA, acting as important mediators of intercellular communication. Given the advantages of intrinsic targeting properties, lower toxicity and fair stability, EVs show great potential to serve as biomarkers, therapeutic agents and drug delivery carriers. However, EV therapies still face several major challenges before they can be applied clinically, including off-target effect, low accumulation rate and rapid clearance by mononuclear phagocyte system. In this review, we first illustrate the roles of EV in the pathological process of AAA and evaluate its possible clinical applications. We also identify present challenges for EV applications, highlight different strategies of EV engineering and constructions of EV-like nanoparticles, including EV display technology and membrane hybrid technology. These leading-edge techniques have been recently employed in multiple cardiovascular diseases and their promising application in the field of AAA is discussed.
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Affiliation(s)
- Shan Lu
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Vascular Surgery Institute of Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Ruihan Wang
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Vascular Surgery Institute of Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Weiguo Fu
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Vascular Surgery Institute of Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
- Weiguo Fu
| | - Yi Si
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Vascular Surgery Institute of Fudan University, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
- *Correspondence: Yi Si
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29
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Tang Y, Zhou Y, Fan S, Wen Q. The Multiple Roles and Therapeutic Potential of HSP60 in Cancer. Biochem Pharmacol 2022; 201:115096. [DOI: 10.1016/j.bcp.2022.115096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
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30
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Mohan Viswanathan T, Krishnakumar V, Senthilkumar D, Chitradevi K, Vijayabhaskar R, Rajesh Kannan V, Senthil Kumar N, Sundar K, Kunjiappan S, Babkiewicz E, Maszczyk P, Kathiresan T. Combinatorial Delivery of Gallium (III) Nitrate and Curcumin Complex-Loaded Hollow Mesoporous Silica Nanoparticles for Breast Cancer Treatment. NANOMATERIALS 2022; 12:nano12091472. [PMID: 35564180 PMCID: PMC9105406 DOI: 10.3390/nano12091472] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/13/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022]
Abstract
The main aims in the development of a novel drug delivery vehicle is to efficiently carry therapeutic drugs in the body's circulatory system and successfully deliver them to the targeted site as needed to safely achieve the desired therapeutic effect. In the present study, a passive targeted functionalised nanocarrier was fabricated or wrapped the hollow mesoporous silica nanoparticles with 3-aminopropyl triethoxysilane (APTES) to prepare APTES-coated hollow mesoporous silica nanoparticles (HMSNAP). A nitrogen sorption analysis confirmed that the shape of hysteresis loops is altered, and subsequently the pore volume and pore diameters of GaC-HMSNAP was reduced by around 56 and 37%, respectively, when compared with HMSNAP. The physico-chemical characterisation studies of fabricated HMSNAP, Ga-HMSNAP and GaC-HMSNAP have confirmed their stability. The drug release capacity of the fabricated Ga-HMSNAP and GaC-HMSNAP for delivery of gallium and curcumin was evaluated in the phosphate buffered saline (pH 3.0, 6.0 and 7.4). In an in silico molecular docking study of the gallium-curcumin complex in PDI, calnexin, HSP60, PDK, caspase 9, Akt1 and PTEN were found to be strong binding. In vitro antitumor activity of both Ga-HMSNAP and GaC-HMSNAP treated MCF-7 cells was investigated in a dose and time-dependent manner. The IC50 values of GaC-HMSNAP (25 µM) were significantly reduced when compared with free gallium concentration (40 µM). The mechanism of gallium-mediated apoptosis was analyzed through western blotting and GaC-HMSNAP has increased caspases 9, 6, cleaved caspase 6, PARP, and GSK 3β(S9) in MCF-7 cells. Similarly, GaC-HMSNAP is reduced mitochondrial proteins such as prohibitin1, HSP60, and SOD1. The phosphorylation of oncogenic proteins such as Akt (S473), c-Raf (S249) PDK1 (S241) and induced cell death in MCF-7 cells. Furthermore, the findings revealed that Ga-HMSNAP and GaC-HMSNAP provide a controlled release of loaded gallium, curcumin and their complex. Altogether, our results depicted that GaC-HMNSAP induced cell death through the mitochondrial intrinsic cell death pathway, which could lead to novel therapeutic strategies for breast adenocarcinoma therapy.
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Affiliation(s)
- Thimma Mohan Viswanathan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | - Vaithilingam Krishnakumar
- Department of Microbiology, Bharathidasan University, Tiruchirappalli 620024, India; (V.K.); (V.R.K.)
| | - Dharmaraj Senthilkumar
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | - Kaniraja Chitradevi
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | | | - Velu Rajesh Kannan
- Department of Microbiology, Bharathidasan University, Tiruchirappalli 620024, India; (V.K.); (V.R.K.)
| | | | - Krishnan Sundar
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | - Selvaraj Kunjiappan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | - Ewa Babkiewicz
- Department of Hydrobiology, Faculty of Biology, University of Warsaw, 02-089 Warsaw, Poland; (E.B.); (P.M.)
| | - Piotr Maszczyk
- Department of Hydrobiology, Faculty of Biology, University of Warsaw, 02-089 Warsaw, Poland; (E.B.); (P.M.)
| | - Thandavarayan Kathiresan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
- Correspondence: ; Tel.: +91-4563-289042; Fax: +91-4563-289322
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31
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Molecular mechanisms and consequences of mitochondrial permeability transition. Nat Rev Mol Cell Biol 2022; 23:266-285. [PMID: 34880425 DOI: 10.1038/s41580-021-00433-y] [Citation(s) in RCA: 291] [Impact Index Per Article: 97.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2021] [Indexed: 12/29/2022]
Abstract
Mitochondrial permeability transition (mPT) is a phenomenon that abruptly causes the flux of low molecular weight solutes (molecular weight up to 1,500) across the generally impermeable inner mitochondrial membrane. The mPT is mediated by the so-called mitochondrial permeability transition pore (mPTP), a supramolecular entity assembled at the interface of the inner and outer mitochondrial membranes. In contrast to mitochondrial outer membrane permeabilization, which mostly activates apoptosis, mPT can trigger different cellular responses, from the physiological regulation of mitophagy to the activation of apoptosis or necrosis. Although there are several molecular candidates for the mPTP, its molecular nature remains contentious. This lack of molecular data was a significant setback that prevented mechanistic insight into the mPTP, pharmacological targeting and the generation of informative animal models. In recent years, experimental evidence has highlighted mitochondrial F1Fo ATP synthase as a participant in mPTP formation, although a molecular model for its transition to the mPTP is still lacking. Recently, the resolution of the F1Fo ATP synthase structure by cryogenic electron microscopy led to a model for mPTP gating. The elusive molecular nature of the mPTP is now being clarified, marking a turning point for understanding mitochondrial biology and its pathophysiological ramifications. This Review provides an up-to-date reference for the understanding of the mammalian mPTP and its cellular functions. We review current insights into the molecular mechanisms of mPT and validated observations - from studies in vivo or in artificial membranes - on mPTP activity and functions. We end with a discussion of the contribution of the mPTP to human disease. Throughout the Review, we highlight the multiple unanswered questions and, when applicable, we also provide alternative interpretations of the recent discoveries.
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Lee YG, Park DH, Chae YC. Role of Mitochondrial Stress Response in Cancer Progression. Cells 2022; 11:cells11050771. [PMID: 35269393 PMCID: PMC8909674 DOI: 10.3390/cells11050771] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/13/2022] [Accepted: 02/17/2022] [Indexed: 02/07/2023] Open
Abstract
Mitochondria are subcellular organelles that are a hub for key biological processes, such as bioenergetic, biosynthetic, and signaling functions. Mitochondria are implicated in all oncogenic processes, from malignant transformation to metastasis and resistance to chemotherapeutics. The harsh tumor environment constantly exposes cancer cells to cytotoxic stressors, such as nutrient starvation, low oxygen, and oxidative stress. Excessive or prolonged exposure to these stressors can cause irreversible mitochondrial damage, leading to cell death. To survive hostile microenvironments that perturb mitochondrial function, cancer cells activate a stress response to maintain mitochondrial protein and genome integrity. This adaptive mechanism, which is closely linked to mitochondrial function, enables rapid adjustment and survival in harsh environmental conditions encountered during tumor dissemination, thereby promoting cancer progression. In this review, we describe how the mitochondria stress response contributes to the acquisition of typical malignant traits and highlight the potential of targeting the mitochondrial stress response as an anti-cancer therapeutic strategy.
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Affiliation(s)
- Yu Geon Lee
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea; (Y.G.L.); (D.H.P.)
- Korea Food Research Institute, Wanju 55365, Korea
| | - Do Hong Park
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea; (Y.G.L.); (D.H.P.)
| | - Young Chan Chae
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea; (Y.G.L.); (D.H.P.)
- Correspondence: ; Tel.: +82-52-217-2524 or +82-52-217-2638
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Wang G, Fan Y, Cao P, Tan K. Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges. Cell Biosci 2022; 12:18. [PMID: 35180892 PMCID: PMC8857832 DOI: 10.1186/s13578-022-00747-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 01/18/2022] [Indexed: 02/08/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved protective transcriptional response that maintains mitochondrial proteostasis by inducing the expression of mitochondrial chaperones and proteases in response to various stresses. The UPRmt-mediated transcriptional program requires the participation of various upstream signaling pathways and molecules. The factors regulating the UPRmt in Caenorhabditis elegans (C. elegans) and mammals are both similar and different. Cancer cells, as malignant cells with uncontrolled proliferation, are exposed to various challenges from endogenous and exogenous stresses. Therefore, in cancer cells, the UPRmt is hijacked and exploited for the repair of mitochondria and the promotion of tumor growth, invasion and metastasis. In this review, we systematically introduce the inducers of UPRmt, the biological processes in which UPRmt participates, the mechanisms regulating the UPRmt in C. elegans and mammals, cross-tissue signal transduction of the UPRmt and the roles of the UPRmt in promoting cancer initiation and progression. Disrupting proteostasis in cancer cells by targeting UPRmt constitutes a novel anticancer therapeutic strategy.
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Affiliation(s)
- Ge Wang
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Hebei, 050024, China.,Department of Human Anatomy, Histology and Embryology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, 100191, China
| | - Yumei Fan
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Hebei, 050024, China
| | - Pengxiu Cao
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Hebei, 050024, China
| | - Ke Tan
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Hebei, 050024, China.
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Gu LF, Chen JQ, Lin QY, Yang YZ. Roles of mitochondrial unfolded protein response in mammalian stem cells. World J Stem Cells 2021; 13:737-752. [PMID: 34367475 PMCID: PMC8316864 DOI: 10.4252/wjsc.v13.i7.737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/13/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPRmt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPRmt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported, the roles of the UPRmt in stem cells are not fully understood. The roles and functions of the UPRmt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPRmt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.
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Affiliation(s)
- Li-Fang Gu
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jia-Qi Chen
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Qing-Yin Lin
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yan-Zhou Yang
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750001, Ningxia Hui Autonomous Region, China.
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Zhang B, Fan Y, Cao P, Tan K. Multifaceted roles of HSF1 in cell death: A state-of-the-art review. Biochim Biophys Acta Rev Cancer 2021; 1876:188591. [PMID: 34273469 DOI: 10.1016/j.bbcan.2021.188591] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/24/2021] [Accepted: 07/11/2021] [Indexed: 02/08/2023]
Abstract
Cell death is a common and active process that is involved in various biological processes, including organ development, morphogenesis, maintaining tissue homeostasis and eliminating potentially harmful cells. Abnormal regulation of cell death significantly contributes to tumor development, progression and chemoresistance. The mechanisms of cell death are complex and involve not only apoptosis and necrosis but also their cross-talk with other types of cell death, such as autophagy and the newly identified ferroptosis. Cancer cells are chronically exposed to various stresses, such as lack of oxygen and nutrients, immune responses, dysregulated metabolism and genomic instability, all of which lead to activation of heat shock factor 1 (HSF1). In response to heat shock, oxidative stress and proteotoxic stresses, HSF1 upregulates transcription of heat shock proteins (HSPs), which act as molecular chaperones to protect normal cells from stresses and various diseases. Accumulating evidence suggests that HSF1 regulates multiple types of cell death through different signaling pathways as well as expression of distinct target genes in cancer cells. Here, we review the current understanding of the potential roles and molecular mechanism of HSF1 in regulating apoptosis, autophagy and ferroptosis. Deciphering HSF1-regulated signaling pathways and target genes may help in the development of new targeted anti-cancer therapeutic strategies.
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Affiliation(s)
- Bingwei Zhang
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China; Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Yumei Fan
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China
| | - Pengxiu Cao
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China
| | - Ke Tan
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
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Guo J, Zhu S, Deng H, Xu R. HSP60-knockdown suppresses proliferation in colorectal cancer cells via activating the adenine/AMPK/mTOR signaling pathway. Oncol Lett 2021; 22:630. [PMID: 34267822 PMCID: PMC8258614 DOI: 10.3892/ol.2021.12891] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 05/28/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is the fourth most lethal cancer in the world. Heat shock protein 60 (HSP60), a mitochondrial chaperone that maintains mitochondrial proteostasis, is highly expressed in tumors compared with in paracancerous tissues, suggesting that high HSP60 expression benefits tumor growth. To determine the effects of HSP60 expression on tumor progression, stable HSP60-knockdown HCT116 cells were constructed in the present study, revealing that knockdown of HSP60 inhibited cell proliferation. Proteomic analysis demonstrated that mitochondrial proteins were downregulated, indicating that knockdown of HSP60 disrupted mitochondrial homeostasis. Metabolomic analysis demonstrated that cellular adenine levels were >30-fold higher in HSP60-knockdown cells than in control cells. It was further confirmed that elevated adenine activated the AMPK signaling pathway, which inhibited mTOR-regulated protein synthesis to slow down cell proliferation. Overall, the current results provide a valuable resource for understanding mitochondrial function in CRC, suggesting that HSP60 may be a potential target for CRC intervention.
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Affiliation(s)
- Jianying Guo
- School of Nursing, Binzhou Medical University, Yantai, Shandong 264003, P.R. China.,Key Laboratory of Bioinformatics, Ministry of Education, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China
| | - Songbiao Zhu
- Key Laboratory of Bioinformatics, Ministry of Education, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China
| | - Haiteng Deng
- Key Laboratory of Bioinformatics, Ministry of Education, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China
| | - Renhua Xu
- School of Nursing, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
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Sun B, Li G, Yu Q, Liu D, Tang X. HSP60 in cancer: a promising biomarker for diagnosis and a potentially useful target for treatment. J Drug Target 2021; 30:31-45. [PMID: 33939586 DOI: 10.1080/1061186x.2021.1920025] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Heat shock proteins (HSPs), most of which are molecular chaperones, are highly conserved proteins produced by cells under physiological stress or pathological conditions. HSP60 (57-69 kDa) can promote or inhibit cell apoptosis through different mechanisms, and its abnormal expression is also related to tumour cell metastasis and drug resistance. In recent years, HSP60 has received increasing attention in the field of cancer research due to its potential as a diagnostic and prognostic biomarker or therapeutic target. However, in different types of cancer, the specific mechanisms of abnormally expressed HSP60 in tumour carcinogenesis and drug resistance are complicated and still require further study. In this article, we comprehensively review the regulative mechanisms of HSP60 on apoptosis, its applications as a cancer diagnostic biomarker and a therapeutic target, evidence of involvement in tumour resistance and the applications of exosomal HSP60 in liquid biopsy. By evaluating the current findings of HSP60 in cancer research, we highlight some core issues that need to be addressed for the use of HSP60 as a diagnostic or prognostic biomarker and therapeutic target in certain types of cancer.
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Affiliation(s)
- Bo Sun
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Ganghui Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Qing Yu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Dongchun Liu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Xing Tang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
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38
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Ray AM, Salim N, Stevens M, Chitre S, Abdeen S, Washburn A, Sivinski J, O'Hagan HM, Chapman E, Johnson SM. Exploiting the HSP60/10 chaperonin system as a chemotherapeutic target for colorectal cancer. Bioorg Med Chem 2021; 40:116129. [PMID: 33971488 DOI: 10.1016/j.bmc.2021.116129] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 11/17/2022]
Abstract
Over the past few decades, an increasing variety of molecular chaperones have been investigated for their role in tumorigenesis and as potential chemotherapeutic targets; however, the 60 kDa Heat Shock Protein (HSP60), along with its HSP10 co-chaperone, have received little attention in this regard. In the present study, we investigated two series of our previously developed inhibitors of the bacterial homolog of HSP60/10, called GroEL/ES, for their selective cytotoxicity to cancerous over non-cancerous colorectal cells. We further developed a third "hybrid" series of analogs to identify new candidates with superior properties than the two parent scaffolds. Using a series of well-established HSP60/10 biochemical screens and cell-viability assays, we identified 24 inhibitors (14%) that exhibited > 3-fold selectivity for targeting colorectal cancer over non-cancerous cells. Notably, cell viability EC50 results correlated with the relative expression of HSP60 in the mitochondria, suggesting a potential for this HSP60-targeting chemotherapeutic strategy as emerging evidence indicates that HSP60 is up-regulated in colorectal cancer tumors. Further examination of five lead candidates indicated their ability to inhibit the clonogenicity and migration of colorectal cancer cells. These promising results are the most thorough analysis and first reported instance of HSP60/10 inhibitors being able to selectively target colorectal cancer cells and highlight the potential of the HSP60/10 chaperonin system as a viable chemotherapeutic target.
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Affiliation(s)
- Anne-Marie Ray
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Nilshad Salim
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Mckayla Stevens
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Siddhi Chitre
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Sanofar Abdeen
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Alex Washburn
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States
| | - Jared Sivinski
- The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., PO Box 210207, Tucson, AZ 85721, United States
| | - Heather M O'Hagan
- Indiana University School of Medicine, Medical Sciences Program and Department of Medical and Molecular Genetics, 1001 East 3rd St., Bloomington, IN 47405, United States
| | - Eli Chapman
- The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., PO Box 210207, Tucson, AZ 85721, United States
| | - Steven M Johnson
- Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
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Lallier M, Marchandet L, Moukengue B, Charrier C, Baud’huin M, Verrecchia F, Ory B, Lamoureux F. Molecular Chaperones in Osteosarcoma: Diagnosis and Therapeutic Issues. Cells 2021; 10:cells10040754. [PMID: 33808130 PMCID: PMC8067202 DOI: 10.3390/cells10040754] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/12/2021] [Accepted: 03/25/2021] [Indexed: 12/16/2022] Open
Abstract
Osteosarcoma (OS) is the most common form of primary bone tumor affecting mainly children and young adults. Despite therapeutic progress, the 5-year survival rate is 70%, but it drops drastically to 30% for poor responders to therapies or for patients with metastases. Identifying new therapeutic targets is thus essential. Heat Shock Proteins (HSPs) are the main effectors of Heat Shock Response (HSR), the expression of which is induced by stressors. HSPs are a large family of proteins involved in the folding and maturation of other proteins in order to maintain proteostasis. HSP overexpression is observed in many cancers, including breast, prostate, colorectal, lung, and ovarian, as well as OS. In this article we reviewed the significant role played by HSPs in molecular mechanisms leading to OS development and progression. HSPs are directly involved in OS cell proliferation, apoptosis inhibition, migration, and drug resistance. We focused on HSP27, HSP60, HSP70 and HSP90 and summarized their potential clinical uses in OS as either biomarkers for diagnosis or therapeutic targets. Finally, based on different types of cancer, we consider the advantage of targeting heat shock factor 1 (HSF1), the major transcriptional regulator of HSPs in OS.
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Affiliation(s)
- Morgane Lallier
- UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, INSERM, Université de Nantes, 44035 Nantes, France; (M.L.); (L.M.); (B.M.); (C.C.); (M.B.); (F.V.); (B.O.)
| | - Louise Marchandet
- UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, INSERM, Université de Nantes, 44035 Nantes, France; (M.L.); (L.M.); (B.M.); (C.C.); (M.B.); (F.V.); (B.O.)
| | - Brice Moukengue
- UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, INSERM, Université de Nantes, 44035 Nantes, France; (M.L.); (L.M.); (B.M.); (C.C.); (M.B.); (F.V.); (B.O.)
| | - Celine Charrier
- UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, INSERM, Université de Nantes, 44035 Nantes, France; (M.L.); (L.M.); (B.M.); (C.C.); (M.B.); (F.V.); (B.O.)
| | - Marc Baud’huin
- UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, INSERM, Université de Nantes, 44035 Nantes, France; (M.L.); (L.M.); (B.M.); (C.C.); (M.B.); (F.V.); (B.O.)
- CHU Nantes, 44035 Nantes, France
| | - Franck Verrecchia
- UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, INSERM, Université de Nantes, 44035 Nantes, France; (M.L.); (L.M.); (B.M.); (C.C.); (M.B.); (F.V.); (B.O.)
| | - Benjamin Ory
- UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, INSERM, Université de Nantes, 44035 Nantes, France; (M.L.); (L.M.); (B.M.); (C.C.); (M.B.); (F.V.); (B.O.)
| | - François Lamoureux
- UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, INSERM, Université de Nantes, 44035 Nantes, France; (M.L.); (L.M.); (B.M.); (C.C.); (M.B.); (F.V.); (B.O.)
- Correspondence:
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Han JM, Sohng JK, Lee WH, Oh TJ, Jung HJ. Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells. Int J Mol Sci 2021; 22:ijms22052473. [PMID: 33804393 PMCID: PMC7957809 DOI: 10.3390/ijms22052473] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/12/2021] [Accepted: 02/22/2021] [Indexed: 01/02/2023] Open
Abstract
We recently discovered a novel nargenicin A1 analog, 23-demethyl 8,13-deoxynargenicin (compound 9), with potential anti-cancer and anti-angiogenic activities against human gastric adenocarcinoma (AGS) cells. To identify the key molecular targets of compound 9, that are responsible for its biological activities, the changes in proteome expression in AGS cells following compound 9 treatment were analyzed using two-dimensional gel electrophoresis (2-DE), followed by MALDI/TOF/MS. Analyses using chemical proteomics and western blotting revealed that compound 9 treatment significantly suppressed the expression of cyclophilin A (CypA), a member of the immunophilin family. Furthermore, compound 9 downregulated CD147-mediated mitogen-activated protein kinase (MAPK) signaling pathway, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) by inhibiting the expression of CD147, the cellular receptor of CypA. Notably, the responses of AGS cells to CypA knockdown were significantly correlated with the anticancer and antiangiogenic effects of compound 9. CypA siRNAs reduced the expression of CD147 and phosphorylation of JNK and ERK1/2. In addition, the suppressive effects of CypA siRNAs on proliferation, migration, invasion, and angiogenesis induction of AGS cells were associated with G2/M cell cycle arrest, caspase-mediated apoptosis, inhibition of MMP-9 and MMP-2 expression, inactivation of PI3K/AKT/mTOR pathway, and inhibition of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. The specific interaction between compound 9 and CypA was also confirmed using the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) approaches. Moreover, in silico docking analysis revealed that the structure of compound 9 was a good fit for the cyclosporin A binding cavity of CypA. Collectively, these findings provide a novel molecular basis for compound 9-mediated suppression of gastric cancer progression through the targeting of CypA.
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Affiliation(s)
- Jang Mi Han
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan 31460, Korea; (J.M.H.); (J.K.S.); (W.-H.L.); (T.-J.O.)
| | - Jae Kyung Sohng
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan 31460, Korea; (J.M.H.); (J.K.S.); (W.-H.L.); (T.-J.O.)
- Department of Pharmaceutical Engineering and Biotechnology, Sun Moon University, Asan 31460, Korea
| | - Woo-Haeng Lee
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan 31460, Korea; (J.M.H.); (J.K.S.); (W.-H.L.); (T.-J.O.)
| | - Tae-Jin Oh
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan 31460, Korea; (J.M.H.); (J.K.S.); (W.-H.L.); (T.-J.O.)
- Department of Pharmaceutical Engineering and Biotechnology, Sun Moon University, Asan 31460, Korea
- Genome-Based BioIT Convergence Institute, Asan 31460, Korea
| | - Hye Jin Jung
- Department of Life Science and Biochemical Engineering, Sun Moon University, Asan 31460, Korea; (J.M.H.); (J.K.S.); (W.-H.L.); (T.-J.O.)
- Department of Pharmaceutical Engineering and Biotechnology, Sun Moon University, Asan 31460, Korea
- Genome-Based BioIT Convergence Institute, Asan 31460, Korea
- Correspondence: ; Tel.: +82-41-530-2354; Fax: +82-41-530-2939
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Abstract
The association of leishmaniasis and malignancies in human and animal models has been highlighted in recent years. The misdiagnosis of coexistence of leishmaniasis and cancer and the use of common drugs in the treatment of such diseases prompt us to further survey the molecular biology of Leishmania parasites and cancer cells. The information regarding common expressed proteins, as possible therapeutic targets, in Leishmania parasites and cancer cells is scarce. Therefore, the current study reviews proteins, and investigates the regulation and functions of several key proteins in Leishmania parasites and cancer cells. The up- and down-regulations of such proteins were mostly related to survival, development, pathogenicity, metabolic pathways and vital signalling in Leishmania parasites and cancer cells. The presence of common expressed proteins in Leishmania parasites and cancer cells reveals valuable information regarding the possible shared mechanisms of pathogenicity and opportunities for therapeutic targeting in leishmaniasis and cancers in the future.
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Mandal JP, Shiue CN, Chen YC, Lee MC, Yang HH, Chang HH, Hu CT, Liao PC, Hui LC, You RI, Wu WS. PKCδ mediates mitochondrial ROS generation and oxidation of HSP60 to relieve RKIP inhibition on MAPK pathway for HCC progression. Free Radic Biol Med 2021; 163:69-87. [PMID: 33307168 DOI: 10.1016/j.freeradbiomed.2020.12.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/25/2020] [Accepted: 12/01/2020] [Indexed: 12/15/2022]
Abstract
Both protein kinase C (PKC) and reactive oxygen species (ROS) are well-known signaling messengers cross-talking with each other to activate mitogen-activated protein kinases (MAPKs) for progression of hepatocellular carcinoma (HCC). However, the underlying mechanisms are not well elucidated. Especially, whether mitochondrial ROS (mtROS) is involved and how it triggers MAPK signaling are intriguing. In this study, we found mtROS generation and phosphorylation of MAPKs were mediated by PKCδ in HCCs treated with the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Heat shock protein 60 (HSP60), one of the chaperones in mitochondria was the major protein oxidized in TPA-treated HCCs. Moreover, depletion of HSP60 or expression of HSP60 cysteine mutant prevented TPA-induced phosphorylation of MAPKs. To delineate how HSP60 mediated MAPK activation, the role of Raf kinase inhibitor protein (RKIP), a negative regulator of MAPK, was investigated. TPA dissociated RKIP from HSP60 in both mitochondria and cytosol, concurrently with translocation of HSP60 and MAPK from mitochondria to cytosol, which was associated with robust phosphorylation of MAPKs in the cytosol. Moreover, TPA induced opposite phenotypical changes of HCCs, G1 cell cycle arrest, and cell migration, which were prevented by mtROS scavengers and depletion of PKCδ and HSP60. Consistently, TPA increased the migration-related genes, hydrogen peroxide inducible clone5, matrix metalloproteinase-1/3, lamininγ2, and suppressed the cell cycle regulator cyclin E1 (CCNE1) via PKCδ/mtROS/HSP60/MAPK-axis. Finally, c-jun and c-fos were required for TPA-induced expression of the migration-related genes and a novel microRNA, miR-6134, was responsible for TPA-induced suppression of CCNE1. In conclusion, PKCδ cross-talked with mtROS to trigger HSP60 oxidation for release of RKIP to activate MAPK, regulating gene expression for migration, and G1 cell cycle arrest in HCC. Targeted therapy aiming at key players like PKCδ, RKIP, and HSP60 is promising for preventing HCC progression.
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Affiliation(s)
| | - Chiou-Nan Shiue
- Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan.
| | - Yen-Cheng Chen
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical foundation, Hualien, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Ming-Che Lee
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical foundation, Hualien, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Hsueh-Hui Yang
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan.
| | - Hsin-Hou Chang
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan; Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan.
| | - Chi-Tan Hu
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan; Division of Gastroenterology, Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical foundation, Hualien, Taiwan; Research Centre for Hepatology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical foundation, Hualien, Taiwan.
| | - Pei-Chen Liao
- Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan.
| | - Lin-Ching Hui
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Ren-In You
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Wen-Sheng Wu
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical foundation, Hualien, Taiwan; Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
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Brain Tumor-Derived Extracellular Vesicles as Carriers of Disease Markers: Molecular Chaperones and MicroRNAs. APPLIED SCIENCES-BASEL 2020. [DOI: 10.3390/app10196961] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Primary and metastatic brain tumors are usually serious conditions with poor prognosis, which reveal the urgent need of developing rapid diagnostic tools and efficacious treatments. To achieve these objectives, progress must be made in the understanding of brain tumor biology, for example, how they resist natural defenses and therapeutic intervention. One resistance mechanism involves extracellular vesicles that are released by tumors to meet target cells nearby or distant via circulation and reprogram them by introducing their cargo. This consists of different molecules among which are microRNAs (miRNAs) and molecular chaperones, the focus of this article. miRNAs modify target cells in the immune system to avoid antitumor reaction and chaperones are key survival molecules for the tumor cell. Extracellular vesicles cargo reflects the composition and metabolism of the original tumor cell; therefore, it is a source of markers, including the miRNAs and chaperones discussed in this article, with potential diagnostic and prognostic value. This and their relatively easy availability by minimally invasive procedures (e.g., drawing venous blood) illustrate the potential of extracellular vesicles as useful materials to manage brain tumor patients. Furthermore, understanding extracellular vesicles circulation and interaction with target cells will provide the basis for using this vesicle for delivering therapeutic compounds to selected tumor cells.
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44
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Wang L, Xu X, Jiang Z, You Q. Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery. Acta Pharm Sin B 2020; 10:1904-1925. [PMID: 33163343 PMCID: PMC7606112 DOI: 10.1016/j.apsb.2020.01.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/10/2019] [Accepted: 01/20/2020] [Indexed: 12/14/2022] Open
Abstract
Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level, which acts as an orientation to develop drugs with new mechanisms. The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein–protein interactions (PPIs) with their client proteins. With the help of molecular chaperone machinery, the processes of protein folding, trafficking, quality control and degradation of client proteins could be arranged properly. The core members of molecular chaperones, including heat shock proteins (HSPs) family and their co-chaperones, are emerging as potential drug targets since they are involved in numerous disease conditions. Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones, co-chaperones and clients is attracting more and more attention. These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases. Here, we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.
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Affiliation(s)
- Lei Wang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaoli Xu
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Zhengyu Jiang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors. Tel./fax: +86 25 83271351.
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors. Tel./fax: +86 25 83271351.
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45
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Circulating HSPs Levels and Risk of Human Gastrointestinal Related Cancers: A Systematic Review and Meta-analysis. Int J Pept Res Ther 2020. [DOI: 10.1007/s10989-019-09942-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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46
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Krishnan-Sivadoss I, Mijares-Rojas IA, Villarreal-Leal RA, Torre-Amione G, Knowlton AA, Guerrero-Beltrán CE. Heat shock protein 60 and cardiovascular diseases: An intricate love-hate story. Med Res Rev 2020; 41:29-71. [PMID: 32808366 PMCID: PMC9290735 DOI: 10.1002/med.21723] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 12/23/2022]
Abstract
Cardiovascular diseases (CVDs) are the result of complex pathophysiological processes in the tissues comprising the heart and blood vessels. Inflammation is the main culprit for the development of cardiovascular dysfunction, and it may be traced to cellular stress events including apoptosis, oxidative and shear stress, and cellular and humoral immune responses, all of which impair the system's structure and function. An intracellular chaperone, heat shock protein 60 (HSP60) is an intriguing example of a protein that may both be an ally and a foe for cardiovascular homeostasis; on one hand providing protection against cellular injury, and on the other triggering damaging responses through innate and adaptive immunity. In this review we will discuss the functions of HSP60 and its effects on cells and the immune system regulation, only to later address its implications in the development and progression of CVD. Lastly, we summarize the outcome of various studies targeting HSP60 as a potential therapeutic strategy for cardiovascular and other diseases.
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Affiliation(s)
- Indumathi Krishnan-Sivadoss
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Medicina Cardiovascular y Metabolómica, Monterrey, Nuevo León, México
| | - Iván A Mijares-Rojas
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Medicina Cardiovascular y Metabolómica, Monterrey, Nuevo León, México
| | - Ramiro A Villarreal-Leal
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Medicina Cardiovascular y Metabolómica, Monterrey, Nuevo León, México
| | - Guillermo Torre-Amione
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Medicina Cardiovascular y Metabolómica, Monterrey, Nuevo León, México.,Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, Texas
| | - Anne A Knowlton
- Veterans Affairs Medical Center, Sacramento, California, USA.,Department of Internal Medicine, Molecular and Cellular Cardiology, Cardiovascular Division, University of California, Davis, California, USA.,Department of Pharmacology, University of California, Davis, California, USA
| | - C Enrique Guerrero-Beltrán
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Medicina Cardiovascular y Metabolómica, Monterrey, Nuevo León, México.,Tecnologico de Monterrey, Hospital Zambrano Hellion, TecSalud, Centro de Investigación Biomédica, San Pedro Garza García, Nuevo León, México
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47
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Rodriguez A, Von Salzen D, Holguin BA, Bernal RA. Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease. Front Mol Biosci 2020; 7:159. [PMID: 32766281 PMCID: PMC7381220 DOI: 10.3389/fmolb.2020.00159] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 06/24/2020] [Indexed: 01/21/2023] Open
Abstract
Several neurological disorders have been linked to mutations in chaperonin genes and more specifically to the HSPD1 gene. In humans, HSPD1 encodes the mitochondrial Heat Shock Protein 60 (mtHsp60) chaperonin, which carries out essential protein folding reactions that help maintain mitochondrial and cellular homeostasis. It functions as a macromolecular complex that provides client proteins an environment that favors proper folding in an ATP-dependent manner. It has been established that mtHsp60 plays a crucial role in the proper folding of mitochondrial proteins involved in ATP producing pathways. Recently, various single-point mutations in the mtHsp60 encoding gene have been directly linked to neuropathies and paraplegias. Individuals who harbor mtHsp60 mutations that negatively impact its folding ability display phenotypes with highly compromised muscle and neuron cells. Carriers of these mutations usually develop neuropathies and paraplegias at different stages of their lives mainly characterized by leg stiffness and weakness as well as degeneration of spinal cord nerves. These phenotypes are likely due to hindered energy producing pathways involved in cellular respiration resulting in ATP deprived cells. Although the complete protein folding mechanism of mtHsp60 is not well understood, recent work suggests that several of these mutations act by destabilizing the oligomeric stability of mtHsp60. Here, we discuss recent studies that highlight key aspects of the mtHsp60 mechanism with a focus on some of the known disease-causing point mutations, D29G and V98I, and their effect on the protein folding reaction cycle.
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Affiliation(s)
| | | | | | - Ricardo A. Bernal
- Department of Chemistry and Biochemistry, The University of Texas at El Paso, El Paso, TX, United States
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48
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Bonora M, Patergnani S, Ramaccini D, Morciano G, Pedriali G, Kahsay AE, Bouhamida E, Giorgi C, Wieckowski MR, Pinton P. Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology. Biomolecules 2020; 10:biom10070998. [PMID: 32635556 PMCID: PMC7408088 DOI: 10.3390/biom10070998] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/29/2020] [Accepted: 07/02/2020] [Indexed: 12/13/2022] Open
Abstract
Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca2+, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation.
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Affiliation(s)
- Massimo Bonora
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (S.P.); (D.R.); (G.M.); (G.P.); (A.E.K.); (E.B.); (C.G.)
- Correspondence: (M.B.); (P.P.)
| | - Simone Patergnani
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (S.P.); (D.R.); (G.M.); (G.P.); (A.E.K.); (E.B.); (C.G.)
| | - Daniela Ramaccini
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (S.P.); (D.R.); (G.M.); (G.P.); (A.E.K.); (E.B.); (C.G.)
| | - Giampaolo Morciano
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (S.P.); (D.R.); (G.M.); (G.P.); (A.E.K.); (E.B.); (C.G.)
- Maria Cecilia Hospital, GVM Care & Research, Via Corriera 1, Cotignola, 48033 Ravenna, Italy
| | - Gaia Pedriali
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (S.P.); (D.R.); (G.M.); (G.P.); (A.E.K.); (E.B.); (C.G.)
- Maria Cecilia Hospital, GVM Care & Research, Via Corriera 1, Cotignola, 48033 Ravenna, Italy
| | - Asrat Endrias Kahsay
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (S.P.); (D.R.); (G.M.); (G.P.); (A.E.K.); (E.B.); (C.G.)
| | - Esmaa Bouhamida
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (S.P.); (D.R.); (G.M.); (G.P.); (A.E.K.); (E.B.); (C.G.)
| | - Carlotta Giorgi
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (S.P.); (D.R.); (G.M.); (G.P.); (A.E.K.); (E.B.); (C.G.)
| | - Mariusz R. Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 3 Pasteur Str., 02-093 Warsaw, Poland;
| | - Paolo Pinton
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (S.P.); (D.R.); (G.M.); (G.P.); (A.E.K.); (E.B.); (C.G.)
- Maria Cecilia Hospital, GVM Care & Research, Via Corriera 1, Cotignola, 48033 Ravenna, Italy
- Correspondence: (M.B.); (P.P.)
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49
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Altinoz MA, Ucal Y, Yilmaz MC, Kiris İ, Ozisik O, Sezerman U, Ozpinar A, Elmaci İ. Progesterone at high doses reduces the growth of U87 and A172 glioblastoma cells: Proteomic changes regarding metabolism and immunity. Cancer Med 2020; 9:5767-5780. [PMID: 32590878 PMCID: PMC7433824 DOI: 10.1002/cam4.3223] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/24/2020] [Accepted: 05/15/2020] [Indexed: 12/16/2022] Open
Abstract
While pregnancy may accelerate glioblastoma multiforme (GBM) growth, parity and progesterone (P4) containing treatments (ie, hormone replacement therapy) reduce the risk of GBM development. In parallel, low and high doses of P4 exert stimulating and inhibitory actions on GBM growth, respectively. The mechanisms behind the high‐dose P4‐suppression of GBM growth is unknown. In the present study, we assessed the changes in growth and proteomic profiles when high‐dose P4 (100 and 300 µM) was administered in human U87 and A172 GBM cell lines. The xCELLigence system was used to examine cell growth when different concentrations of P4 (20, 50, 100, and 300 µM) was administered. The protein profiles were determined by two‐dimensional gel electrophoresis in both cell lines when 100 and 300 µM P4 were administered. Finally, the pathways enriched by the differentially expressed proteins were assessed using bioinformatic tools. Increasing doses of P4 blocked the growth of both GBM cells. We identified 26 and 51 differentially expressed proteins (fc > 2) in A172 and U87 cell lines treated with P4, respectively. Only the pro‐tumorigenic mitochondrial ornithine aminotransferase and anti‐apoptotic mitochondrial 60 kDa heat shock protein were downregulated in A172 cell line and U87 cell line when treated with P4, respectively. Detoxification of reactive oxygen species, cellular response to stress, glucose metabolism, and immunity‐related proteins were altered in P4‐treated GBM cell lines. The paradox on the effect of low and high doses of P4 on GBM growth is gaining attention. The mechanism related to the high dose of P4 on GBM growth can be explained by the alterations in detoxification mechanisms, stress, and immune response and glucose metabolism. P4 suppresses GBM growth and as it is nontoxic in comparison to classical chemotherapeutics, it can be used as a new strategy in GBM treatment in the future.
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Affiliation(s)
- Meric A Altinoz
- Department of Medical Biochemistry, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Yasemin Ucal
- Department of Medical Biochemistry, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Muazzez C Yilmaz
- Department of Medical Biochemistry, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - İrem Kiris
- Department of Medical Biochemistry, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Ozan Ozisik
- Medical Genetics, Aix Marseille University, Inserm, MMG, Marseille, France
| | - Ugur Sezerman
- Department of Biostatistics and Medical Informatics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Aysel Ozpinar
- Department of Medical Biochemistry, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - İlhan Elmaci
- Department of Neurosurgery, Acibadem Maslak Hospital and School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
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50
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Caruso Bavisotto C, Alberti G, Vitale AM, Paladino L, Campanella C, Rappa F, Gorska M, Conway de Macario E, Cappello F, Macario AJL, Marino Gammazza A. Hsp60 Post-translational Modifications: Functional and Pathological Consequences. Front Mol Biosci 2020; 7:95. [PMID: 32582761 PMCID: PMC7289027 DOI: 10.3389/fmolb.2020.00095] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 04/24/2020] [Indexed: 12/15/2022] Open
Abstract
Hsp60 is a chaperone belonging to the Chaperonins of Group I and typically functions inside mitochondria in which, together with the co-chaperonin Hsp10, maintains protein homeostasis. In addition to this canonical role, Hsp60 plays many others beyond the mitochondria, for instance in the cytosol, plasma-cell membrane, extracellular space, and body fluids. These non-canonical functions include participation in inflammation, autoimmunity, carcinogenesis, cell replication, and other cellular events in health and disease. Thus, Hsp60 is a multifaceted molecule with a wide range of cellular and tissue locations and functions, which is noteworthy because there is only one hsp60 gene. The question is by what mechanism this protein can become multifaceted. Likely, one factor contributing to this diversity is post-translational modification (PTM). The amino acid sequence of Hsp60 contains many potential phosphorylation sites, and other PTMs are possible such as O-GlcNAcylation, nitration, acetylation, S-nitrosylation, citrullination, oxidation, and ubiquitination. The effect of some of these PTMs on Hsp60 functions have been examined, for instance phosphorylation has been implicated in sperm capacitation, docking of H2B and microtubule-associated proteins, mitochondrial dysfunction, tumor invasiveness, and delay or facilitation of apoptosis. Nitration was found to affect the stability of the mitochondrial permeability transition pore, to inhibit folding ability, and to perturb insulin secretion. Hyperacetylation was associated with mitochondrial failure; S-nitrosylation has an impact on mitochondrial stability and endothelial integrity; citrullination can be pro-apoptotic; oxidation has a role in the response to cellular injury and in cell migration; and ubiquitination regulates interaction with the ubiquitin-proteasome system. Future research ought to determine which PTM causes which variations in the Hsp60 molecular properties and functions, and which of them are pathogenic, causing chaperonopathies. This is an important topic considering the number of acquired Hsp60 chaperonopathies already cataloged, many of which are serious diseases without efficacious treatment.
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Affiliation(s)
- Celeste Caruso Bavisotto
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy.,Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
| | - Giusi Alberti
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy
| | - Alessandra Maria Vitale
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy
| | - Letizia Paladino
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy
| | - Claudia Campanella
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy
| | - Francesca Rappa
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy
| | - Magdalena Gorska
- Department of Medical Chemistry, Medical University of Gdańsk, Gdańsk, Poland
| | - Everly Conway de Macario
- Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.,Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD, United States
| | - Francesco Cappello
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy.,Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
| | - Alberto J L Macario
- Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.,Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD, United States
| | - Antonella Marino Gammazza
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Italy
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