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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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Zu X, Chen S, Li Z, Hao L, Fu W, Zhang H, Yin Z, Wang Y, Wang J. SPI1 activates mitochondrial unfolded response signaling to inhibit chondrocyte senescence and relieves osteoarthritis. Bone Res 2025; 13:47. [PMID: 40229258 PMCID: PMC11997156 DOI: 10.1038/s41413-025-00421-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 04/16/2025] Open
Abstract
Chondrocyte senescence is a critical pathological hallmark of osteoarthritis (OA). Aberrant mechanical stress is considered a pivotal determinant in chondrocyte aging; however, the precise underlying mechanism remains elusive. Our findings demonstrate that SPI1 plays a significant role in counteracting chondrocyte senescence and inhibiting OA progression. SPI1 binds to the PERK promoter, thereby promoting its transcriptional activity. Importantly, PERK, rather than GCN2, facilitates eIF2α phosphorylation, activating the mitochondrial unfolded protein response (UPRmt) and impeding chondrocyte senescence. Deficiency of SPI1 in mechanical overload-induced mice leads to diminished UPRmt activation and accelerated OA progression. Intra-articular injection of adenovirus vectors overexpressing SPI1 and PERK effectively mitigates cartilage degeneration. In summary, our study elucidates the crucial regulatory role of SPI1 in the pathogenesis of chondrocyte senescence by activating UPRmt signaling through PERK, which may present a novel therapeutic target for treating OA. SPI1 alleviates the progression of OA by inhibiting mechanical stress-induced chondrocyte senescence through mitochondrial UPR signaling.
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Affiliation(s)
- Xiangyu Zu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Anhui, China
| | - Shenghong Chen
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Anhui, China
- Anhui Province Key Laboratory of zoonoses, Anhui Medical University, Hefei, China
| | - Zhengyuan Li
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Anhui, China
- Anhui Province Key Laboratory of zoonoses, Anhui Medical University, Hefei, China
| | - Lin Hao
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Anhui, China
- Anhui Province Key Laboratory of zoonoses, Anhui Medical University, Hefei, China
| | - Wenhan Fu
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Anhui, China
- Anhui Province Key Laboratory of zoonoses, Anhui Medical University, Hefei, China
| | - Hui Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Anhui, China
| | - Zongsheng Yin
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Anhui, China.
| | - Yin Wang
- Department of Wound Repair & Plastic and Aesthetic Surgery, the First Affiliated Hospital of Anhui Medical University, Anhui, China.
- Anhui Public Health Clinical Center, Anhui, China.
| | - Jun Wang
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Anhui, China.
- Anhui Province Key Laboratory of zoonoses, Anhui Medical University, Hefei, China.
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Woytash JA, Kumar R, Chaudhary AK, Donnelly C, Wojtulski A, Bethu M, Wang J, Spernyak J, Bross P, Yadav N, Inigo JR, Chandra D. Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer. Oncogene 2025; 44:820-834. [PMID: 39690273 DOI: 10.1038/s41388-024-03261-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 12/19/2024]
Abstract
The mitochondrial unfolded protein response (UPRmt) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPRmt in aggressive and resistant prostate cancer is not clearly defined. We show that castration-resistant neuroendocrine prostate cancer (CRPC-NE) harbored highly dysfunctional oxidative phosphorylation (OXPHOS) Complexes. However, biochemical and protein analyses of CRPC-NE tumors showed upregulation of nuclear-encoded OXPHOS proteins and UPRmt in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPRmt heat shock protein 60 (HSP60) reduced neuroendocrine prostate cancer (NEPC) growth in vivo as well as reverted NEPC cells to a more epithelial-like state. HSP60-dependent aggressive NEPC phenotypes was associated with upregulation of β-catenin signaling both in cancer cells and in vivo tumors. HSP60 expression rendered enrichment of aggressive prostate cancer signatures and metastatic potential were inhibited upon suppression of UPRmt. We discovered that UPRmt promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPRmt resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPRmt promotes mitochondrial health via upregulating β-catenin signaling and UPRmt represents viable therapeutic target for NEPC.
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Affiliation(s)
- Jordan Alyse Woytash
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Rahul Kumar
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Ajay K Chaudhary
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Cullan Donnelly
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Adam Wojtulski
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Murali Bethu
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Jianmin Wang
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Joseph Spernyak
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Peter Bross
- Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, 8200, Aarhus N, Denmark
| | - Neelu Yadav
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Joseph R Inigo
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Dhyan Chandra
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
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Stutz C, Gegout PY, Bloch C, Özçelik H, Anton N, Tabti R, Désaubry L, Huck O, Petit C. The prohibitin ligand IN44 decreases Porphyromonas gingivalis mediated inflammation. BMC Oral Health 2024; 24:1534. [PMID: 39709363 DOI: 10.1186/s12903-024-05209-2] [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: 09/07/2024] [Accepted: 11/14/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Periodontitis is an inflammatory disease causing destruction of periodontal tissues. Controlling inflammation is crucial for periodontitis treatment. Prohibitins (PHBs) are emerging targets in the treatment of inflammatory diseases. To identify compounds that would alleviate periodontitis, several small molecules that directly target PHBs and display various pharmacological activities were screened to decrease Porphyromonas gingivalis induced inflammation. Indeed, IN44, a new PHB ligand that has been shown to inhibit STAT3 and NF-kB signaling, suggesting that it may alleviate periodontitis. This study aimed to assess IN44's impact on inflammation elicited by P. gingivalis. METHODS In vitro, IN44 cytotoxicity was tested on periodontal cells with AlamarBlue and Live/Dead assays. Its effect on cytokines and mitochondrial ROS production were evaluated using ELISA and Mitosox assay. In mouse, systemic inflammation and experimental periodontitis were induced to assess IN44's therapeutic effects. RESULTS In vitro, IN44 (50 µM) showed no cytotoxicity on periodontal cells. It significantly reduced pro-inflammatory cytokine secretion and mitochondrial ROS in P. gingivalis-infected epithelial cells. Proteome analysis on infected epithelial cells revealed modulation of HSP60 and Akt expression by IN44. In vivo, IN44 demonstrated anti-inflammatory effects in a mouse model of systemic inflammation induced by P. gingivalis, and it improved periodontal healing. CONCLUSION These findings suggest that PHBs may warrant consideration as therapeutic targets for periodontitis and possibly other inflammatory disorders.
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Affiliation(s)
- Céline Stutz
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67084, France
| | - Pierre-Yves Gegout
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67084, France
- Faculté de Chirurgie-dentaire, Dental Faculty, Université de Strasbourg, 8 rue Sainte-Elisabeth, Strasbourg, 67000, France
- Pôle de médecine et chirurgie Bucco-dentaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, 67000, France
| | - Chloé Bloch
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67084, France
| | - Hayriye Özçelik
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67084, France
| | - Nicolas Anton
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67084, France
| | - Redouane Tabti
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67084, France
| | - Laurent Désaubry
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67084, France
| | - Olivier Huck
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67084, France.
- Faculté de Chirurgie-dentaire, Dental Faculty, Université de Strasbourg, 8 rue Sainte-Elisabeth, Strasbourg, 67000, France.
- Pôle de médecine et chirurgie Bucco-dentaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, 67000, France.
| | - Catherine Petit
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67084, France
- Faculté de Chirurgie-dentaire, Dental Faculty, Université de Strasbourg, 8 rue Sainte-Elisabeth, Strasbourg, 67000, France
- Pôle de médecine et chirurgie Bucco-dentaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, 67000, France
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Soldatov V, Venediktov A, Belykh A, Piavchenko G, Naimzada MD, Ogneva N, Kartashkina N, Bushueva O. Chaperones vs. oxidative stress in the pathobiology of ischemic stroke. Front Mol Neurosci 2024; 17:1513084. [PMID: 39723236 PMCID: PMC11668803 DOI: 10.3389/fnmol.2024.1513084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 11/20/2024] [Indexed: 12/28/2024] Open
Abstract
As many proteins prioritize functionality over constancy of structure, a proteome is the shortest stave in the Liebig's barrel of cell sustainability. In this regard, both prokaryotes and eukaryotes possess abundant machinery supporting the quality of the proteome in healthy and stressful conditions. This machinery, namely chaperones, assists in folding, refolding, and the utilization of client proteins. The functions of chaperones are especially important for brain cells, which are highly sophisticated in terms of structural and functional organization. Molecular chaperones are known to exert beneficial effects in many brain diseases including one of the most threatening and widespread brain pathologies, ischemic stroke. However, whether and how they exert the antioxidant defense in stroke remains unclear. Herein, we discuss the chaperones shown to fight oxidative stress and the mechanisms of their antioxidant action. In ischemic stroke, during intense production of free radicals, molecular chaperones preserve the proteome by interacting with oxidized proteins, regulating imbalanced mitochondrial function, and directly fighting oxidative stress. For instance, cells recruit Hsp60 and Hsp70 to provide proper folding of newly synthesized proteins-these factors are required for early ischemic response and to refold damaged polypeptides. Additionally, Hsp70 upregulates some dedicated antioxidant pathways such as FOXO3 signaling. Small HSPs decrease oxidative stress via attenuation of mitochondrial function through their involvement in the regulation of Nrf- (Hsp22), Akt and Hippo (Hsp27) signaling pathways as well as mitophagy (Hsp27, Hsp22). A similar function has also been proposed for the Sigma-1 receptor, contributing to the regulation of mitochondrial function. Some chaperones can prevent excessive formation of reactive oxygen species whereas Hsp90 is suggested to be responsible for pro-oxidant effects in ischemic stroke. Finally, heat-resistant obscure proteins (Hero) are able to shield client proteins, thus preventing their possible over oxidation.
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Affiliation(s)
- Vladislav Soldatov
- Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia
| | - Artem Venediktov
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Andrei Belykh
- Pathophysiology Department, Kursk State Medical University, Kursk, Russia
- Research Institute of General Pathology, Kursk State Medical University, Kursk, Russia
| | - Gennadii Piavchenko
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Mukhammad David Naimzada
- Research Institute of Experimental Medicine, Kursk State Medical University, Kursk, Russia
- Laboratory of Public Health Indicators Analysis and Health Digitalization, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Nastasya Ogneva
- Scientific Center of Biomedical Technologies, Federal Medical and Biological Agency of Russia, Moscow, Russia
| | - Natalia Kartashkina
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Olga Bushueva
- Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk, Russia
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russia
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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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Li J, Zhang S, Li C, Zhang X, Shan Y, Zhang Z, Bo H, Zhang Y. Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis. Sci Rep 2024; 14:21154. [PMID: 39256490 PMCID: PMC11387812 DOI: 10.1038/s41598-024-72088-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 09/03/2024] [Indexed: 09/12/2024] Open
Abstract
Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.
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Affiliation(s)
- Jialin Li
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin, 301617, China
| | - Sheng Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin, 301617, China
- Tianjin Hospital, Tianjin, 300299, China
| | - Can Li
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin, 301617, China
- Department of sport science, Tianjin normal university, Tianjin, 300387, China
| | - Xiaoxia Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin, 301617, China
| | - Yuhui Shan
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin, 301617, China
| | - Ziyi Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin, 301617, China.
| | - Hai Bo
- Department of Military Training Medicines, Logistics University of Chinese People's Armed Police Force, Tianjin, 300162, China.
| | - Yong Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin, 301617, China.
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9
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Nakamura ET, Park A, Pereira MA, Kikawa D, Tustumi F. Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer: A systematic review and meta-analysis. World J Gastrointest Oncol 2024; 16:1578-1595. [PMID: 38660660 PMCID: PMC11037039 DOI: 10.4251/wjgo.v16.i4.1578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/24/2023] [Accepted: 01/23/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Heat shock proteins (HSPs) are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overexpressed in many cancers. The prognostic significance of HSPs and their regulatory factors, such as heat shock factor 1 (HSF1) and CHIP, are poorly understood. AIM To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer. METHODS A systematic review was conducted in accordance with PRISMA recommendations (PROSPERO: CRD42022370653), on Embase, PubMed, Cochrane, and LILACS. Cohort, case-control, and cross-sectional studies of patients with esophagus or esophagogastric cancer were included. HSP-positive patients were compared with HSP-negative, and the endpoints analyzed were lymph node metastasis, tumor depth, distant metastasis, and overall survival (OS). HSPs were stratified according to the HSP family, and the summary risk difference (RD) was calculated using a random-effect model. RESULTS The final selection comprised 27 studies, including esophageal squamous cell carcinoma (21), esophagogastric adenocarcinoma (5), and mixed neoplasms (1). The pooled sample size was 3465 patients. HSP40 and 60 were associated with a higher 3-year OS [HSP40: RD = 0.22; 95% confidence interval (CI): 0.09-0.35; HSP60: RD = 0.33; 95%CI: 0.17-0.50], while HSF1 was associated with a poor 3-year OS (RD = -0.22; 95%CI: -0.32 to -0.12). The other HSP families were not associated with long-term survival. HSF1 was associated with a higher probability of lymph node metastasis (RD = -0.16; 95%CI: -0.29 to -0.04). HSP40 was associated with a lower probability of lymph node dissemination (RD = 0.18; 95%CI: 0.03-0.33). The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis. CONCLUSION The expression levels of certain families of HSP, such as HSP40 and 60 and HSF1, are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.
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Affiliation(s)
- Eric Toshiyuki Nakamura
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Amanda Park
- Department of Evidence-Based Medicine, Centro Universitário Lusíada, Centre for Evidence-Based Medicine, Centro Universitário Lusíada (UNILUS), Santos, Brazil
| | - Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
| | - Daniel Kikawa
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Francisco Tustumi
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo 05652900, Brazil
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10
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Kunachowicz D, Król-Kulikowska M, Raczycka W, Sleziak J, Błażejewska M, Kulbacka J. Heat Shock Proteins, a Double-Edged Sword: Significance in Cancer Progression, Chemotherapy Resistance and Novel Therapeutic Perspectives. Cancers (Basel) 2024; 16:1500. [PMID: 38672583 PMCID: PMC11048091 DOI: 10.3390/cancers16081500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Heat shock proteins (Hsps) are involved in one of the adaptive mechanisms protecting cells against environmental and metabolic stress. Moreover, the large role of these proteins in the carcinogenesis process, as well as in chemoresistance, was noticed. This review aims to draw attention to the possibilities of using Hsps in developing new cancer therapy methods, as well as to indicate directions for future research on this topic. In order to discuss this matter, a thorough review of the latest scientific literature was carried out, taking into account the importance of selected proteins from the Hsp family, including Hsp27, Hsp40, Hsp60, Hsp70, Hsp90 and Hsp110. One of the more characteristic features of all Hsps is that they play a multifaceted role in cancer progression, which makes them an obvious target for modern anticancer therapy. Some researchers emphasize the importance of directly inhibiting the action of these proteins. In turn, others point to their possible use in the design of cancer vaccines, which would work by inducing an immune response in various types of cancer. Due to these possibilities, it is believed that the use of Hsps may contribute to the progress of oncoimmunology, and thus help in the development of modern anticancer therapies, which would be characterized by higher effectiveness and lower toxicity to the patients.
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Affiliation(s)
- Dominika Kunachowicz
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (D.K.); (M.K.-K.)
| | - Magdalena Król-Kulikowska
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (D.K.); (M.K.-K.)
| | - Wiktoria Raczycka
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (W.R.); (J.S.); (M.B.)
| | - Jakub Sleziak
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (W.R.); (J.S.); (M.B.)
| | - Marta Błażejewska
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (W.R.); (J.S.); (M.B.)
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine Santariškių g. 5, LT-08406 Vilnius, Lithuania
- DIVE IN AI, 53-307 Wroclaw, Poland
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11
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Aluksanasuwan S, Somsuan K, Ngoenkam J, Chutipongtanate S, Pongcharoen S. Potential association of HSPD1 with dysregulations in ribosome biogenesis and immune cell infiltration in lung adenocarcinoma: An integrated bioinformatic approach. Cancer Biomark 2024; 39:155-170. [PMID: 37694354 PMCID: PMC11091585 DOI: 10.3233/cbm-220442] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 07/03/2023] [Indexed: 09/12/2023]
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) is a major histological subtype of lung cancer with a high mortality rate worldwide. Heat shock protein family D member 1 (HSPD1, also known as HSP60) is reported to be increased in tumor tissues of lung cancer patients compared with healthy control tissues. OBJECTIVE We aimed to investigate the roles of HSPD1 in prognosis, carcinogenesis, and immune infiltration in LUAD using an integrative bioinformatic analysis. METHODS HSPD1 expression in LUAD was investigated in several transcriptome-based and protein databases. Survival analysis was performed using the KM plotter and OSluca databases, while prognostic significance was independently confirmed through univariate and multivariate analyses. Integrative gene interaction network and enrichment analyses of HSPD1-correlated genes were performed to investigate the roles of HSPD1 in LUAD carcinogenesis. TIMER and TISIDB were used to analyze correlation between HSPD1 expression and immune cell infiltration. RESULTS The mRNA and protein expressions of HSPD1 were higher in LUAD compared with normal tissues. High HSPD1 expression was associated with male gender and LUAD with advanced stages. High HSPD1 expression was an independent prognostic factor associated with poor survival in LUAD patients. HSPD1-correlated genes with prognostic impact were mainly involved in aberrant ribosome biogenesis, while LUAD patients with high HSPD1 expression had low tumor infiltrations of activated and immature B cells and CD4+ T cells. CONCLUSIONS HSPD1 may play a role in the regulation of ribosome biogenesis and B cell-mediated immunity in LUAD. It could serve as a predictive biomarker for prognosis and immunotherapy response in LUAD.
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Affiliation(s)
- Siripat Aluksanasuwan
- School of Medicine, Mae Fah Luang University, Chiang Rai, Thailand
- Cancer and Immunology Research Unit (CIRU), Mae Fah Luang University, Chiang Rai, Thailand
| | - Keerakarn Somsuan
- School of Medicine, Mae Fah Luang University, Chiang Rai, Thailand
- Cancer and Immunology Research Unit (CIRU), Mae Fah Luang University, Chiang Rai, Thailand
| | - Jatuporn Ngoenkam
- Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand
| | - Somchai Chutipongtanate
- MILCH and Novel Therapeutics Lab, Division of Epidemiology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Sutatip Pongcharoen
- Division of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok, Thailand
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12
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Cilleros-Holgado P, Gómez-Fernández D, Piñero-Pérez R, Romero-Domínguez JM, Reche-López D, López-Cabrera A, Álvarez-Córdoba M, Munuera-Cabeza M, Talaverón-Rey M, Suárez-Carrillo A, Romero-González A, Sánchez-Alcázar JA. Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases. Biomolecules 2023; 13:1789. [PMID: 38136659 PMCID: PMC10741690 DOI: 10.3390/biom13121789] [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: 11/18/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Jose Antonio Sánchez-Alcázar
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (P.C.-H.); (D.G.-F.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.); (M.Á.-C.); (M.M.-C.); (M.T.-R.); (A.S.-C.); (A.R.-G.)
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13
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Payea MJ, Dar SA, Malla S, Maragkakis M. Ribonucleic Acid-Mediated Control of Protein Translation Under Stress. Antioxid Redox Signal 2023; 39:374-389. [PMID: 37470212 PMCID: PMC10443204 DOI: 10.1089/ars.2023.0233] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 05/30/2023] [Indexed: 07/21/2023]
Abstract
Significance: The need of cells to constantly respond to endogenous and exogenous stress has necessitated the evolution of pathways to counter the deleterious effects of stress and to restore cellular homeostasis. The inability to activate a timely and adequate response can lead to disease and is a hallmark of aging. Besides protein-coding genes, cells contain a plethora of noncoding regulatory elements that allow cells to respond rapidly and efficiently to external stimuli by activating highly specific and tightly controlled mechanisms. Many of these programs converge on the regulation of translation, one of the most energy-consuming processes in cells. Recent Advances: The noncoding dimension of translational regulation includes short and long noncoding ribonucleic acids (ncRNAs), as well as messenger RNA features, such as the sequence and modification status of the 5' and 3' untranslated regions (UTRs), that do not change the amino acid sequence of the produced protein. Critical Issues: In this review, we discuss the regulatory role of the nonprotein-coding components of translation under stress, particularly oxidative stress. We conclude that the regulation of translation through ncRNAs, UTRs, and nucleotide modifications is emerging as a critical component of the stress response. Future Directions: Further areas of study using long-read sequencing technologies will be discussed. Antioxid. Redox Signal. 39, 374-389.
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Affiliation(s)
- Matthew J. Payea
- Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
| | - Showkat A. Dar
- Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
| | - Sulochan Malla
- Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
| | - Manolis Maragkakis
- Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
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14
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Lin W, Niu R, Park SM, Zou Y, Kim SS, Xia X, Xing S, Yang Q, Sun X, Yuan Z, Zhou S, Zhang D, Kwon HJ, Park S, Il Kim C, Koo H, Liu Y, Wu H, Zheng M, Yoo H, Shi B, Park JB, Yin J. IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis. Nat Commun 2023; 14:1578. [PMID: 36949068 PMCID: PMC10033905 DOI: 10.1038/s41467-023-37306-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 03/10/2023] [Indexed: 03/24/2023] Open
Abstract
Diffuse infiltration is the main reason for therapeutic resistance and recurrence in glioblastoma (GBM). However, potential targeted therapies for GBM stem-like cell (GSC) which is responsible for GBM invasion are limited. Herein, we report Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase like Orphan Receptor 1 (ROR1), as a promising target for GSC invasion. Using a GSC-derived brain tumor model, GSCs were characterized into invasive or non-invasive subtypes, and RNA sequencing analysis revealed that IGFBP5 was differentially expressed between these two subtypes. GSC invasion capacity was inhibited by IGFBP5 knockdown and enhanced by IGFBP5 overexpression both in vitro and in vivo, particularly in a patient-derived xenograft model. IGFBP5 binds to ROR1 and facilitates ROR1/HER2 heterodimer formation, followed by inducing CREB-mediated ETV5 and FBXW9 expression, thereby promoting GSC invasion and tumorigenesis. Importantly, using a tumor-specific targeting and penetrating nanocapsule-mediated delivery of CRISPR/Cas9-based IGFBP5 gene editing significantly suppressed GSC invasion and downstream gene expression, and prolonged the survival of orthotopic tumor-bearing mice. Collectively, our data reveal that IGFBP5-ROR1/HER2-CREB signaling axis as a potential GBM therapeutic target.
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Affiliation(s)
- Weiwei Lin
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
- Research Institute, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
- Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Rui Niu
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Seong-Min Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
- Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Republic of Korea
| | - Yan Zou
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
- Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine & Health Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - Sung Soo Kim
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
| | - Xue Xia
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Songge Xing
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Qingshan Yang
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Xinhong Sun
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Zheng Yuan
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Shuchang Zhou
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Dongya Zhang
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Hyung Joon Kwon
- Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
| | - Saewhan Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
| | - Chan Il Kim
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
| | - Harim Koo
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
| | - Yang Liu
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Haigang Wu
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Meng Zheng
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Heon Yoo
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
- Research Institute, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea
| | - Bingyang Shi
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China.
- Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine & Health Sciences, Macquarie University, Sydney, NSW, 2109, Australia.
| | - Jong Bae Park
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China.
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea.
- Research Institute, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea.
| | - Jinlong Yin
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China.
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea.
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15
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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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16
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Cilleros-Holgado P, Gómez-Fernández D, Piñero-Pérez R, Reche-López D, Álvarez-Córdoba M, Munuera-Cabeza M, Talaverón-Rey M, Povea-Cabello S, Suárez-Carrillo A, Romero-González A, Suárez-Rivero JM, Romero-Domínguez JM, Sánchez-Alcázar JA. mtUPR Modulation as a Therapeutic Target for Primary and Secondary Mitochondrial Diseases. Int J Mol Sci 2023; 24:ijms24021482. [PMID: 36674998 PMCID: PMC9865803 DOI: 10.3390/ijms24021482] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/04/2023] [Accepted: 01/09/2023] [Indexed: 01/14/2023] Open
Abstract
Mitochondrial dysfunction is a key pathological event in many diseases. Its role in energy production, calcium homeostasis, apoptosis regulation, and reactive oxygen species (ROS) balance render mitochondria essential for cell survival and fitness. However, there are no effective treatments for most primary and secondary mitochondrial diseases to this day. Therefore, new therapeutic approaches, such as the modulation of the mitochondrial unfolded protein response (mtUPR), are being explored. mtUPRs englobe several compensatory processes related to proteostasis and antioxidant system mechanisms. mtUPR activation, through an overcompensation for mild intracellular stress, promotes cell homeostasis and improves lifespan and disease alterations in biological models of mitochondrial dysfunction in age-related diseases, cardiopathies, metabolic disorders, and primary mitochondrial diseases. Although mtUPR activation is a promising therapeutic option for many pathological conditions, its activation could promote tumor progression in cancer patients, and its overactivation could lead to non-desired side effects, such as the increased heteroplasmy of mitochondrial DNA mutations. In this review, we present the most recent data about mtUPR modulation as a therapeutic approach, its role in diseases, and its potential negative consequences in specific pathological situations.
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17
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Mulati S, Jiang R, Wang J, Tao Y, Zhang W. 6-Shogaol Exhibits a Promoting Effect with Tax via Binding HSP60 in Non-Small-Cell Lung Cancer. Cells 2022; 11:cells11223678. [PMID: 36429106 PMCID: PMC9688423 DOI: 10.3390/cells11223678] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/07/2022] [Accepted: 11/15/2022] [Indexed: 11/22/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) is a prevalent malignant tumor with high morbidity and mortality rates worldwide. Although surgical resection, adjuvant radiotherapy/chemotherapy, and targeted molecular therapy are the cornerstones of NSCLC treatment, NSCLC is associated with high recurrence rates and drug resistance. This study analyzed the potential targets and pathways of 6-Shogaol (6-SH) in NSCLC, showing that 6-SH binds to heat-shock 60 kDa protein (HSP60) in A549 cells, induces cell apoptosis, and arrests the cell cycle possibly by disrupting the mitochondrial function. HSP60 was identified as the target of 6-SH and 6-SH-induced HSP60 degradation which was mediated by the proteasome. The binding of 6-SH with HSP60 altered its stability, inhibited the ERK, Stat3, PI3K, Akt, and mTOR signaling pathways, and Tax acted synergistically with 6-SH, indicating that 6-SH could be developed as a potential therapeutic agent for an NSCLC treatment.
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18
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Liu XY, Wang YM, Zhang XY, Jia MQ, Duan HQ, Qin N, Chen Y, Yu Y, Duan XC. Alkaloid Derivative ( Z)-3β-Ethylamino-Pregn-17(20)-en Inhibits Triple-Negative Breast Cancer Metastasis and Angiogenesis by Targeting HSP90α. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27207132. [PMID: 36296726 PMCID: PMC9611734 DOI: 10.3390/molecules27207132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/17/2022] [Accepted: 10/19/2022] [Indexed: 11/25/2022]
Abstract
Metastasis is an important cause of cancer-related death. Previous studies in our laboratory found that pregnane alkaloids from Pachysandra terminalis had antimetastatic activity against breast cancer cells. In the current study, we demonstrated that treatment with one of the alkaloid derivatives, (Z)-3β-ethylamino-pregn-17(20)-en (1), led to the downregulation of the HIF-1α/VEGF/VEGFR2 pathway, suppressed the phosphorylation of downstream molecules Akt, mTOR, FAK, and inhibited breast cancer metastasis and angiogenesis both in vitro and in vivo. Furthermore, the antimetastasis and antiangiogenesis effects of 1 treatment (40 mg/kg) were more effective than that of Sorafenib (50 mg/kg). Surface plasmon resonance (SPR) analysis was performed and the result suggested that HSP90α was a direct target of 1. Taken together, our results suggested that compound 1 might represent a candidate antitumor agent for metastatic breast cancer.
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Affiliation(s)
- Xin-Yao Liu
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Yu-Miao Wang
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Xiang-Yu Zhang
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Mei-Qi Jia
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Hong-Quan Duan
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Nan Qin
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Ying Chen
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Yang Yu
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
- Correspondence: (Y.Y.); (X.-C.D.); Tel.: +86-22-83336680 (X.-C.D.); Fax: +86-22-83336560 (X.-C.D.)
| | - Xiao-Chuan Duan
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
- Correspondence: (Y.Y.); (X.-C.D.); Tel.: +86-22-83336680 (X.-C.D.); Fax: +86-22-83336560 (X.-C.D.)
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19
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Bastian PE, Daca A, Płoska A, Kuban-Jankowska A, Kalinowski L, Gorska-Ponikowska M. 2-Methoxyestradiol Damages DNA in Glioblastoma Cells by Regulating nNOS and Heat Shock Proteins. Antioxidants (Basel) 2022; 11:2013. [PMID: 36290736 PMCID: PMC9598669 DOI: 10.3390/antiox11102013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/02/2022] [Accepted: 10/10/2022] [Indexed: 08/18/2023] Open
Abstract
Gliomas are the most prevalent primary tumors of the central nervous system (CNS), accounting for over fifty percent of all primary intracranial neoplasms. Glioblastoma (GBM) is the most prevalent form of malignant glioma and is often incurable. The main distinguishing trait of GBM is the presence of hypoxic regions accompanied by enhanced angiogenesis. 2-Methoxyestradiol (2-ME) is a well-established antiangiogenic and antiproliferative drug. In current clinical studies, 2-ME, known as Panzem, was examined for breast, ovarian, prostate, and multiple myeloma. The SW1088 grade III glioma cell line was treated with pharmacological and physiological doses of 2-ME. The induction of apoptosis and necrosis, oxidative stress, cell cycle arrest, and mitochondrial membrane potential were established by flow cytometry. Confocal microscopy was used to detect DNA damage. The Western blot technique determined the level of nitric oxide synthase and heat shock proteins. Here, for the first time, 2-ME is shown to induce nitro-oxidative stress with the concomitant modulation of heat shock proteins (HSPs) in the SW1088 grade III glioma cell line. Crucial therapeutic strategies for GMB should address both cell proliferation and angiogenesis, and due to the above, 2-ME seems to be a perfect candidate for GBM therapy.
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Affiliation(s)
| | - Agnieszka Daca
- Department of Pathology and Experimental Rheumatology, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Agata Płoska
- Department of Medical Laboratory Diagnostics—Fahrenheit Biobank BBMRI.pl, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland
| | | | - Leszek Kalinowski
- Department of Medical Laboratory Diagnostics—Fahrenheit Biobank BBMRI.pl, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland
- BioTechMed Centre, Department of Mechanics of Materials and Structures, Gdansk University of Technology, Narutowicza Street 11/12, 80-233 Gdansk, Poland
| | - Magdalena Gorska-Ponikowska
- Department of Medical Chemistry, Medical University of Gdansk, 80-210 Gdansk, Poland
- Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, D-70569 Stuttgart, Germany
- Euro-Mediterranean Institute of Science and Technology, 90139 Palermo, Italy
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20
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Hu C, Yang J, Qi Z, Wu H, Wang B, Zou F, Mei H, Liu J, Wang W, Liu Q. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm (Beijing) 2022; 3:e161. [PMID: 35928554 PMCID: PMC9345296 DOI: 10.1002/mco2.161] [Citation(s) in RCA: 222] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 12/12/2022] Open
Abstract
The heat shock proteins (HSPs) are ubiquitous and conserved protein families in both prokaryotic and eukaryotic organisms, and they maintain cellular proteostasis and protect cells from stresses. HSP protein families are classified based on their molecular weights, mainly including large HSPs, HSP90, HSP70, HSP60, HSP40, and small HSPs. They function as molecular chaperons in cells and work as an integrated network, participating in the folding of newly synthesized polypeptides, refolding metastable proteins, protein complex assembly, dissociating protein aggregate dissociation, and the degradation of misfolded proteins. In addition to their chaperone functions, they also play important roles in cell signaling transduction, cell cycle, and apoptosis regulation. Therefore, malfunction of HSPs is related with many diseases, including cancers, neurodegeneration, and other diseases. In this review, we describe the current understandings about the molecular mechanisms of the major HSP families including HSP90/HSP70/HSP60/HSP110 and small HSPs, how the HSPs keep the protein proteostasis and response to stresses, and we also discuss their roles in diseases and the recent exploration of HSP related therapy and diagnosis to modulate diseases. These research advances offer new prospects of HSPs as potential targets for therapeutic intervention.
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Affiliation(s)
- Chen Hu
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- Hefei Cancer HospitalChinese Academy of SciencesHefeiAnhuiP. R. China
| | - Jing Yang
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- Hefei Cancer HospitalChinese Academy of SciencesHefeiAnhuiP. R. China
| | - Ziping Qi
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- Hefei Cancer HospitalChinese Academy of SciencesHefeiAnhuiP. R. China
| | - Hong Wu
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- Hefei Cancer HospitalChinese Academy of SciencesHefeiAnhuiP. R. China
| | - Beilei Wang
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- Hefei Cancer HospitalChinese Academy of SciencesHefeiAnhuiP. R. China
| | - Fengming Zou
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- Hefei Cancer HospitalChinese Academy of SciencesHefeiAnhuiP. R. China
| | - Husheng Mei
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- University of Science and Technology of ChinaHefeiAnhuiP. R. China
| | - Jing Liu
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- Hefei Cancer HospitalChinese Academy of SciencesHefeiAnhuiP. R. China
- University of Science and Technology of ChinaHefeiAnhuiP. R. China
| | - Wenchao Wang
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- Hefei Cancer HospitalChinese Academy of SciencesHefeiAnhuiP. R. China
- University of Science and Technology of ChinaHefeiAnhuiP. R. China
| | - Qingsong Liu
- Anhui Province Key Laboratory of Medical Physics and TechnologyInstitute of Health and Medical TechnologyHefei Institutes of Physical ScienceChinese Academy of SciencesHefeiAnhuiP. R. China
- Hefei Cancer HospitalChinese Academy of SciencesHefeiAnhuiP. R. China
- University of Science and Technology of ChinaHefeiAnhuiP. R. China
- Precision Medicine Research Laboratory of Anhui ProvinceHefeiAnhuiP. R. China
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21
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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: 53] [Impact Index Per Article: 17.7] [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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22
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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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23
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Shkedi A, Taylor IR, Echtenkamp F, Ramkumar P, Alshalalfa M, Rivera-Márquez GM, Moses MA, Shao H, Karnes RJ, Neckers L, Feng F, Kampmann M, Gestwicki JE. Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer. Cell Chem Biol 2022; 29:490-501.e4. [PMID: 35108506 PMCID: PMC8934263 DOI: 10.1016/j.chembiol.2022.01.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/17/2021] [Accepted: 01/11/2022] [Indexed: 11/28/2022]
Abstract
Castration-resistant prostate cancer (CRPC) is associated with an increased reliance on heat shock protein 70 (HSP70), but it is not clear what other protein homeostasis (proteostasis) factors might be involved. To address this question, we performed functional and synthetic lethal screens in four prostate cancer cell lines. These screens confirmed key roles for HSP70, HSP90, and their co-chaperones, but also suggested that the mitochondrial chaperone, HSP60/HSPD1, is selectively required in CRPC cell lines. Knockdown of HSP60 does not impact the stability of androgen receptor (AR) or its variants; rather, it is associated with loss of mitochondrial spare respiratory capacity, partly owing to increased proton leakage. Finally, transcriptional data revealed a correlation between HSP60 levels and poor survival of prostate cancer patients. These findings suggest that re-wiring of the proteostasis network is associated with CRPC, creating selective vulnerabilities that might be targeted to treat the disease.
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Affiliation(s)
- Arielle Shkedi
- Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Isabelle R Taylor
- Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Frank Echtenkamp
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Poornima Ramkumar
- Department of Biochemistry and Biophysics and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Mohamed Alshalalfa
- Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Génesis M Rivera-Márquez
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Michael A Moses
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Hao Shao
- Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA
| | | | - Len Neckers
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Felix Feng
- Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Martin Kampmann
- Department of Biochemistry and Biophysics and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Jason E Gestwicki
- Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
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24
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Cyran AM, Zhitkovich A. Heat Shock Proteins and HSF1 in Cancer. Front Oncol 2022; 12:860320. [PMID: 35311075 PMCID: PMC8924369 DOI: 10.3389/fonc.2022.860320] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 02/07/2022] [Indexed: 12/23/2022] Open
Abstract
Fitness of cells is dependent on protein homeostasis which is maintained by cooperative activities of protein chaperones and proteolytic machinery. Upon encountering protein-damaging conditions, cells activate the heat-shock response (HSR) which involves HSF1-mediated transcriptional upregulation of a group of chaperones - the heat shock proteins (HSPs). Cancer cells experience high levels of proteotoxic stress due to the production of mutated proteins, aneuploidy-induced excess of components of multiprotein complexes, increased translation rates, and dysregulated metabolism. To cope with this chronic state of proteotoxic stress, cancers almost invariably upregulate major components of HSR, including HSF1 and individual HSPs. Some oncogenic programs show dependence or coupling with a particular HSR factor (such as frequent coamplification of HSF1 and MYC genes). Elevated levels of HSPs and HSF1 are typically associated with drug resistance and poor clinical outcomes in various malignancies. The non-oncogene dependence ("addiction") on protein quality controls represents a pancancer target in treating human malignancies, offering a potential to enhance efficacy of standard and targeted chemotherapy and immune checkpoint inhibitors. In cancers with specific dependencies, HSR components can serve as alternative targets to poorly druggable oncogenic drivers.
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Affiliation(s)
- Anna M Cyran
- Legoretta Cancer Center, Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, United States
| | - Anatoly Zhitkovich
- Legoretta Cancer Center, Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, United States
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25
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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: 27] [Impact Index Per Article: 9.0] [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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26
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Wang Q, Karvelsson ST, Kotronoulas A, Gudjonsson T, Halldorsson S, Rolfsson O. Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) is upregulated in breast epithelial-mesenchymal transition and responds to oxidative stress. Mol Cell Proteomics 2021; 21:100185. [PMID: 34923141 PMCID: PMC8803663 DOI: 10.1016/j.mcpro.2021.100185] [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: 05/26/2021] [Revised: 10/20/2021] [Accepted: 12/13/2021] [Indexed: 12/02/2022] Open
Abstract
Breast cancer cells that have undergone partial epithelial–mesenchymal transition (EMT) are believed to be more invasive than cells that have completed EMT. To study metabolic reprogramming in different mesenchymal states, we analyzed protein expression following EMT in the breast epithelial cell model D492 with single-shot LFQ supported by a SILAC proteomics approach. The D492 EMT cell model contains three cell lines: the epithelial D492 cells, the mesenchymal D492M cells, and a partial mesenchymal, tumorigenic variant of D492 that overexpresses the oncogene HER2. The analysis classified the D492 and D492M cells as basal-like and D492HER2 as claudin-low. Comparative analysis of D492 and D492M to tumorigenic D492HER2 differentiated metabolic markers of migration from those of invasion. Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) was one of the top dysregulated enzymes in D492HER2. Gene expression analysis of the cancer genome atlas showed that GFPT2 expression was a characteristic of claudin-low breast cancer. siRNA-mediated knockdown of GFPT2 influenced the EMT marker vimentin and both cell growth and invasion in vitro and was accompanied by lowered metabolic flux through the hexosamine biosynthesis pathway (HBP). Knockdown of GFPT2 decreased cystathionine and sulfide:quinone oxidoreductase (SQOR) in the transsulfuration pathway that regulates H2S production and mitochondrial homeostasis. Moreover, GFPT2 was within the regulation network of insulin and EGF, and its expression was regulated by reduced glutathione (GSH) and suppressed by the oxidative stress regulator GSK3-β. Our results demonstrate that GFPT2 controls growth and invasion in the D492 EMT model, is a marker for oxidative stress, and associated with poor prognosis in claudin-low breast cancer.
GFPT2 is upregulated following EMT. GFPT2 is a marker for claudin-low breast cancer. GFPT2 affects vimentin, cell proliferation, and cell invasion. GFPT2 responds to oxidative stress. GFPT2 is regulated by insulin and EGF.
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Affiliation(s)
- Qiong Wang
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101 Reykjavik, Iceland
| | - Sigurdur Trausti Karvelsson
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101 Reykjavik, Iceland
| | - Aristotelis Kotronoulas
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101 Reykjavik, Iceland
| | - Thorarinn Gudjonsson
- Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavík, Iceland
| | - Skarphedinn Halldorsson
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101 Reykjavik, Iceland
| | - Ottar Rolfsson
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101 Reykjavik, Iceland.
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27
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Estradiol ameliorates metformin-inhibited Sertoli cell proliferation via AMPK/TSC2/mTOR signaling pathway. Theriogenology 2021; 175:7-22. [PMID: 34481229 DOI: 10.1016/j.theriogenology.2021.08.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/31/2021] [Accepted: 08/25/2021] [Indexed: 12/15/2022]
Abstract
Metformin is a commonly used for treating type 2 diabetes and it acts on a variety of organs including the male reproductive system. 17β-estradiol plays an important role in Sertoli cell (SC) proliferation which determines the germ cell development and spermatogenesis. The aim of this study is to investigate the effect of metformin on immature chicken SC proliferation and the potential mechanisms by which 17β-estradiol regulate this process. Results showed that metformin significantly inhibited SC proliferation, whereas 17β-estradiol weakened the inhibitory effects of metformin on SC viability, cell growth, and cell cycle progression. SC proliferation-inhibiting effect of metformin exposure was regulated by decreasing adenosine triphosphate level and respiratory enzyme activity in the mitochondria; this process was possibly mediated by the adenosine monophosphate-activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2)/mammalian target of rapamycin (mTOR) signaling pathway, which was regulated by the down-expressed miR-1764 and by the decreased antioxidant enzyme activity and excessive reactive oxygen species generation. In addition, SCs transfected with the miR-1764 agomir led to an improvement of proliferation capacity through down-regulating AMPKα2 level, which further decreased TSC2 expression and induced mTOR activation. However, the anti-proliferative effect of miR-1764 antagomir can be alleviated by 17β-estradiol treatment via the up-expression of miR-1764 in transfected SCs. Our findings suggest appropriate dose of exogenous 17β-estradiol treatment can ameliorate the inhibitory effect of metformin on SC proliferation via the regulation of AMPK/TSC2/mTOR signaling pathway, this might reduce the risk of poor male fertility caused by the abuse of anti-diabetic agents.
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28
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Yang S, Xiao H, Cao L. Recent advances in heat shock proteins in cancer diagnosis, prognosis, metabolism and treatment. Biomed Pharmacother 2021; 142:112074. [PMID: 34426258 DOI: 10.1016/j.biopha.2021.112074] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/13/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023] Open
Abstract
Heat shock proteins (HSPs) are a group of proteins, also known as molecular chaperones, which participate in protein folding and maturation in response to stresses or high temperature. According to their molecular weights, mammalian HSPs are classified into HSP27, HSP40, HSP60, HSP70, HSP90, and large HSPs. Previous studies have revealed that HSPs play important roles in oncogenesis and malignant progression because they can modulate all six hallmark traits of cancer. Because of this, HSPs have been propelled into the spotlight as biomarkers for cancer diagnosis and prognosis, as well as an exciting anticancer drug target. However, the relationship between the expression level of HSPs and their activity and cancer diagnosis, prognosis, metabolism and treatment is not clear and has not been completely established. Herein, this review summarizes and discusses recent advances and perspectives in major HSPs as biomarkers for cancer diagnosis, as regulators for cancer metabolism or as therapeutic targets for cancer therapy, which may provide new directions to improve the accuracy of cancer diagnosis and develop more effective and safer anticancer therapeutics.
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Affiliation(s)
- Shuxian Yang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China; Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China; Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China
| | - Haiyan Xiao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China; Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China; Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China
| | - Li Cao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China; Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China; Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China.
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Caja L, Dadras MS, Mezheyeuski A, Rodrigues-Junior DM, Liu S, Webb AT, Gomez-Puerto MC, Ten Dijke P, Heldin CH, Moustakas A. The protein kinase LKB1 promotes self-renewal and blocks invasiveness in glioblastoma. J Cell Physiol 2021; 237:743-762. [PMID: 34350982 DOI: 10.1002/jcp.30542] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/10/2021] [Accepted: 07/24/2021] [Indexed: 12/13/2022]
Abstract
The role of liver kinase B1 (LKB1) in glioblastoma (GBM) development remains poorly understood. LKB1 may regulate GBM cell metabolism and has been suggested to promote glioma invasiveness. After analyzing LKB1 expression in GBM patient mRNA databases and in tumor tissue via multiparametric immunohistochemistry, we observed that LKB1 was localized and enriched in GBM tumor cells that co-expressed SOX2 and NESTIN stemness markers. Thus, LKB1-specific immunohistochemistry can potentially reveal subpopulations of stem-like cells, advancing GBM patient molecular pathology. We further analyzed the functions of LKB1 in patient-derived GBM cultures under defined serum-free conditions. Silencing of endogenous LKB1 impaired 3D-gliomasphere frequency and promoted GBM cell invasion in vitro and in the zebrafish collagenous tail after extravasation of circulating GBM cells. Moreover, loss of LKB1 function revealed mitochondrial dysfunction resulting in decreased ATP levels. Treatment with the clinically used drug metformin impaired 3D-gliomasphere formation and enhanced cytotoxicity induced by temozolomide, the primary chemotherapeutic drug against GBM. The IC50 of temozolomide in the GBM cultures was significantly decreased in the presence of metformin. This combinatorial effect was further enhanced after LKB1 silencing, which at least partially, was due to increased apoptosis. The expression of genes involved in the maintenance of tumor stemness, such as growth factors and their receptors, including members of the platelet-derived growth factor (PDGF) family, was suppressed after LKB1 silencing. The defect in gliomasphere growth caused by LKB1 silencing was bypassed after supplementing the cells with exogenous PFDGF-BB. Our data support the parallel roles of LKB1 in maintaining mitochondrial homeostasis, 3D-gliomasphere survival, and hindering migration in GBM. Thus, the natural loss of, or pharmacological interference with LKB1 function, may be associated with benefits in patient survival but could result in tumor spread.
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Affiliation(s)
- Laia Caja
- Department of Medical Biochemistry and Microbiology and Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Mahsa Shahidi Dadras
- Department of Medical Biochemistry and Microbiology and Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.,Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Artur Mezheyeuski
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Dorival Mendes Rodrigues-Junior
- Department of Medical Biochemistry and Microbiology and Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Sijia Liu
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Anna Taylor Webb
- Department of Medical Biochemistry and Microbiology and Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.,Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Maria Catalina Gomez-Puerto
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Peter Ten Dijke
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Carl-Henrik Heldin
- Department of Medical Biochemistry and Microbiology and Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology and Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden
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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: 21] [Impact Index Per Article: 5.3] [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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The Triad Hsp60-miRNAs-Extracellular Vesicles in Brain Tumors: Assessing Its Components for Understanding Tumorigenesis and Monitoring Patients. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11062867] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Brain tumors have a poor prognosis and progress must be made for developing efficacious treatments, but for this to occur their biology and interaction with the host must be elucidated beyond current knowledge. What has been learned from other tumors may be applied to study brain tumors, for example, the role of Hsp60, miRNAs, and extracellular vesicles (EVs) in the mechanisms of cell proliferation and dissemination, and resistance to immune attack and anticancer drugs. It has been established that Hsp60 increases in cancer cells, in which it occurs not only in the mitochondria but also in the cytosol and plasma-cell membrane and it is released in EVs into the extracellular space and in circulation. There is evidence suggesting that these EVs interact with cells near and far from their original cell and that this interaction has an impact on the functions of the target cell. It is assumed that this crosstalk between cancer and host cells favors carcinogenesis in various ways. We, therefore, propose to study the triad Hsp60-related miRNAs-EVs in brain tumors and have standardized methods for the purpose. These revealed that EVs with Hsp60 and related miRNAs increase in patients’ blood in a manner that reflects disease status. The means are now available to monitor brain tumor patients by measuring the triad and to dissect its effects on target cells in vitro, and in experimental models in vivo.
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Pan Y, Abdureyim M, Yao Q, Li X. Analysis of Differentially Expressed Genes in Endothelial Cells Following Tumor Cell Adhesion, and the Role of PRKAA2 and miR-124-3p. Front Cell Dev Biol 2021; 9:604038. [PMID: 33681194 PMCID: PMC7933219 DOI: 10.3389/fcell.2021.604038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 01/19/2021] [Indexed: 01/25/2023] Open
Abstract
Tumor cell adhesion to the endothelium is one pattern of tumor-endothelium interaction and a key step during tumor metastasis. Endothelium integrity is an important barrier to prevent tumor invasion and metastasis. Changes in endothelial cells (ECs) due to tumor cell adhesion provide important signaling mechanisms for the angiogenesis and metastasis of tumor cells. However, the changes happened in endothelial cells when tumor-endothelium interactions are still unclear. In this study, we used Affymetrix Gene Chip Human Transcriptome Array 2.0. and quantitative real-time PCR (qPCR) to clarify the detailed gene alteration in endothelial cells adhered by prostate tumor cells PC-3M. A total of 504 differentially expressed mRNAs and 444 lncRNAs were obtained through chip data analysis. Gene Ontology (GO) function analysis showed that differentially expressed genes (DEGs) mainly mediated gland development and DNA replication at the biological level; at the cell component level, they were mainly involved in the mitochondrial inner membrane; and at the molecular function level, DEGs were mainly enriched in ATPase activity and catalytic activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis showed that the DEGs mainly regulated pathways in cancer, cell cycle, pyrimidine metabolism, and the mTOR signaling pathway. Then, we constructed a protein-protein interaction functional network and mRNA-lncRNA interaction network using Cytoscape v3.7.2. to identify core genes, mRNAs, and lncRNAs. The miRNAs targeted by the core mRNA PRKAA2 were predicted using databases (miRDB, RNA22, and Targetscan). The qPCR results showed that miR-124-3p, the predicted target miRNA of PRKAA2, was significantly downregulated in endothelial cells adhered by PC-3M. With a dual luciferase reporter assay, the binding of miR-124-3p with PRKAA2 3'UTR was confirmed. Additionally, by using the knockdown lentiviral vectors of miR-124-3p to downregulate the miR-124-3p expression level in endothelial cells, we found that the expression level of PRKAA2 increased accordingly. Taken together, the adhesion of tumor cells had a significant effect on mRNAs and lncRNAs in the endothelial cells, in which PRKAA2 is a notable changed molecule and miR-124-3p could regulate its expression and function in endothelial cells.
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Affiliation(s)
- Yan Pan
- Department of Pharmacology, Health Science Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Marhaba Abdureyim
- Department of Pharmacology, Health Science Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Qing Yao
- Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, China
| | - Xuejun Li
- Department of Pharmacology, Health Science Center, School of Basic Medical Sciences, Peking University, Beijing, China
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Tang Y, Yang Y, Luo J, Liu S, Zhan Y, Zang H, Zheng H, Zhang Y, Feng J, Fan S, Wen Q. Overexpression of HSP10 correlates with HSP60 and Mcl-1 levels and predicts poor prognosis in non-small cell lung cancer patients. Cancer Biomark 2021; 30:85-94. [PMID: 32986659 PMCID: PMC7990427 DOI: 10.3233/cbm-200410] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND HSP60 and its partner HSP10 are members of heat shock proteins (HSPs) family, which help mitochondrial protein to fold correctly. Mcl-1, a member of the Bcl-2 family, plays a crucial role in regulation of cell apoptosis. Aberrant expression of HSP10, HSP60 and Mcl-1 is involved in the development of many tumors. OBJECTIVE To examine the association between expression of HSP10, HSP60 and Mcl-1 and clinicopathological features of non-small cell lung cancer (NSCLC). METHODS Tissue microarrays including 53 non-cancerous lung tissues (Non-CLT) and 354 surgically resected NSCLC were stained with anti-HSP10, anti-HSP60 and anti-Mcl-1 antibodies respectively by immunohistochemistry. RESULTS Higher expression of HSP10, HSP60 and Mcl-1 was found in NSCLC compared with Non-CLT. Both individual and combined HSP10 and HSP60 expression in patients with clinical stage III was higher than that in stage I ∼ II. Expression of HSP10 showed a positive correlation with HSP60 and Mcl-1. Overall survival time of NSCLC patients was remarkably shorter with elevated expression of HSP10, HSP60 and Mcl-1 alone and in combination. Moreover overexpression of HSP10 and Mcl-1 was poor independent prognostic factor for lung adenocarcinoma patients. CONCLUSIONS High expression of HSP10, HSP60 and Mcl-1 might act as novel biomarker of poor prognosis for NSCLC patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Qiuyuan Wen
- Corresponding author: Qiuyuan Wen, Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China. E-mail:
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Zhu L, Zhou Q, He L, Chen L. Mitochondrial unfolded protein response: An emerging pathway in human diseases. Free Radic Biol Med 2021; 163:125-134. [PMID: 33347985 DOI: 10.1016/j.freeradbiomed.2020.12.013] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/20/2020] [Accepted: 12/10/2020] [Indexed: 12/14/2022]
Abstract
Mitochondrial unfolded protein response (UPRmt) is a mitochondria stress response, which the transcriptional activation programs of mitochondrial chaperone proteins and proteases are initiated to maintain proteostasis in mitochondria. Additionally, the activation of UPRmt delays aging and extends lifespan by maintaining mitochondrial proteostasis. Growing evidences suggests that UPRmt plays an important role in diverse human diseases, especially ageing-related diseases. Therefore, this review focuses on the role of UPRmt in ageing and ageing-related neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease. The activation of UPRmt and the high expression of UPRmt components contribute to longevity extension. The activation of UPRmt may ameliorate Alzheimer's disease, Parkinson's disease and Huntington's disease. Besides, UPRmt is also involved in the occurrence and development of cancers and heart diseases. UPRmt contributes to the growth, invasive and metastasis of cancers. UPRmt has paradoxical roles in heart diseases. UPRmt not only protects against heart damage, but may sometimes aggravates the development of heart diseases. Considering the pleiotropic actions of UPRmt system, targeting UPRmt pathway may be a potent therapeutic avenue for neurodegenerative diseases, cancers and heart diseases.
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Affiliation(s)
- Li Zhu
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
| | - Qionglin Zhou
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
| | - Lu He
- Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang, China.
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China.
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D’Amico D, Fiore R, Caporossi D, Di Felice V, Cappello F, Dimauro I, Barone R. Function and Fiber-Type Specific Distribution of Hsp60 and αB-Crystallin in Skeletal Muscles: Role of Physical Exercise. BIOLOGY 2021; 10:biology10020077. [PMID: 33494467 PMCID: PMC7911561 DOI: 10.3390/biology10020077] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/15/2021] [Accepted: 01/19/2021] [Indexed: 12/19/2022]
Abstract
Simple Summary Skeletal muscle represents about 40% of the body mass in humans and it is a copious and plastic tissue, rich in proteins that are subject to continuous rearrangements. Physical exercise is considered a physiological stressor for different organs, in particular for skeletal muscle, and it is a factor able to stimulate the cellular remodeling processes related to the phenomenon of adaptation. All cells respond to various stress conditions by up-regulating the expression and/or activation of a group of proteins called heat shock proteins (HSPs). Although their expression is induced by several stimuli, they are commonly recognized as HSPs due to the first experiments showing their increased transcription after application of heat shock. These proteins are molecular chaperones mainly involved in assisting protein transport and folding, assembling multimolecular complexes, and triggering protein degradation by proteasome. Among the HSPs, a special attention needs to be devoted to Hsp60 and αB-crystallin, proteins constitutively expressed in the skeletal muscle, where they are known to be important in muscle physiopathology. Therefore, here we provide a critical update on their role in skeletal muscle fibers after physical exercise, highlighting the control of their expression, their biological function, and their specific distribution within skeletal muscle fiber-types. Abstract Skeletal muscle is a plastic and complex tissue, rich in proteins that are subject to continuous rearrangements. Skeletal muscle homeostasis can be affected by different types of stresses, including physical activity, a physiological stressor able to stimulate a robust increase in different heat shock proteins (HSPs). The modulation of these proteins appears to be fundamental in facilitating the cellular remodeling processes related to the phenomenon of training adaptations such as hypertrophy, increased oxidative capacity, and mitochondrial activity. Among the HSPs, a special attention needs to be devoted to Hsp60 and αB-crystallin (CRYAB), proteins constitutively expressed in the skeletal muscle, where their specific features could be highly relevant in understanding the impact of different volumes of training regimes on myofiber types and in explaining the complex picture of exercise-induced mechanical strain and damaging conditions on fiber population. This knowledge could lead to a better personalization of training protocols with an optimal non-harmful workload in populations of individuals with different needs and healthy status. Here, we introduce for the first time to the reader these peculiar HSPs from the perspective of exercise response, highlighting the control of their expression, biological function, and specific distribution within skeletal muscle fiber-types.
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Affiliation(s)
- Daniela D’Amico
- Human Anatomy Section, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (D.D.); (V.D.F.)
- Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch (UTMB), Galveston, TX 77554, USA
| | - Roberto Fiore
- Postgraduate School of Sports Medicine, University Hospital of Palermo, 90127 Palermo, Italy;
| | - Daniela Caporossi
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, 00135 Rome, Italy;
| | - Valentina Di Felice
- Human Anatomy Section, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (D.D.); (V.D.F.)
| | - Francesco Cappello
- Human Anatomy Section, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (D.D.); (V.D.F.)
- Euro-Mediterranean Institutes of Science and Technology (IEMEST), 90139 Palermo, Italy
- Correspondence: (F.C.); (I.D.); (R.B.); Tel.: +39-091-2386-5823 (F.C. & R.B.); +39-06-3673-3562 (I.D.)
| | - Ivan Dimauro
- Department of Movement, Human and Health Sciences, University of Rome Foro Italico, 00135 Rome, Italy;
- Correspondence: (F.C.); (I.D.); (R.B.); Tel.: +39-091-2386-5823 (F.C. & R.B.); +39-06-3673-3562 (I.D.)
| | - Rosario Barone
- Human Anatomy Section, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (D.D.); (V.D.F.)
- Correspondence: (F.C.); (I.D.); (R.B.); Tel.: +39-091-2386-5823 (F.C. & R.B.); +39-06-3673-3562 (I.D.)
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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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Chen Y, Qiao X, Zhang L, Li X, Liu Q. Apelin-13 regulates angiotensin ii-induced Cx43 downregulation and autophagy via the AMPK/mTOR signaling pathway in HL-1 cells. Physiol Res 2020; 69:813-822. [PMID: 32901500 DOI: 10.33549/physiolres.934488] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Atrial fibrillation is associated with atrial remodeling, in which connexin 43 (Cx43) and cell hypertrophy play important roles. In this study, apelin-13, an aliphatic peptide, was used to explore the protective effects of the adenosine monophosphate-activated protein kinase (AMPK)/mTOR signaling pathway on Cx43 expression and autophagy, using murine atrial HL-1 cells. The expression of Cx43, AMPK, B-type natriuretic peptide (BNP) and pathway-related proteins was detected by Western blot analysis. Cellular fluorescence imaging was used to visualize Cx43 distribution and the cytoskeleton. Our results showed that the Cx43 expression was significantly decreased in HL-1 cells treated with angiotensin II but increased in cells additionally treated with apelin-13. Meanwhile, apelin-13 decreased BNP expression and increased AMPK expression. However, the expression of Cx43 and LC3 increased by apelin-13 was inhibited by treatment with compound C, an AMPK inhibitor. In addition, rapamycin, an mTOR inhibitor, promoted the development of autophagy, further inhibited the protective effect on Cx43 expression and increased cell hypertrophy. Thus, apelin-13 enhances Cx43 expression and autophagy via the AMPK/mTOR signaling pathway, and serving as a potential therapeutic target for atrial fibrillation.
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Affiliation(s)
- Y Chen
- Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan, China. , Department of Pathophysiology, Shanxi Medical University, Taiyuan, China.
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Xue W, Men S, Liu R. Rotenone restrains the proliferation, motility and epithelial-mesenchymal transition of colon cancer cells and the tumourigenesis in nude mice via PI3K/AKT pathway. Clin Exp Pharmacol Physiol 2020; 47:1484-1494. [PMID: 32282954 PMCID: PMC7384028 DOI: 10.1111/1440-1681.13320] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 03/15/2020] [Accepted: 03/30/2020] [Indexed: 12/13/2022]
Abstract
Rotenone, a toxic rotenoid compound, has anti-tumour effects on several cancers. This study aims to clarify the effect of rotenone on the proliferation, apoptosis, invasion and migration of colon cancer cells and tumourigenesis in nude mice. The present results show that rotenone significantly inhibited the proliferation, promoted the apoptosis, and suppressed the invasion and migration of colon cancer cells in a dose-dependent manner. Rotenone inhibited PI3K/AKT pathway in LoVo and SW480 cells in a dose-dependent manner. In addition, rotenone regulated the proliferation, apoptosis, invasion, migration and EMT of LoVo and SW480 cells through PI3K/AKT pathway. In colon cancer xenograft mice, rotenone inhibited tumour volume and weight in nude mice, inhibited PI3K/AKT pathway and EMT in vivo. Therefore, rotenone inhibited the proliferation, invasion and migration, promoted the apoptosis of colon cancer cells through PI3K/AKT pathway in vitro, and suppressed the tumourigenesis in nude mice in vivo.
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Affiliation(s)
- Wusong Xue
- Department of AnoretalDongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Siye Men
- Department of General SurgeryDongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Renghai Liu
- Department of AnoretalDongfang HospitalBeijing University of Chinese MedicineBeijingChina
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Sun H, Zou HY, Cai XY, Zhou HF, Li XQ, Xie WJ, Xie WM, Du ZP, Xu LY, Li EM, Wu BL. Network Analyses of the Differential Expression of Heat Shock Proteins in Glioma. DNA Cell Biol 2020; 39:1228-1242. [PMID: 32429692 DOI: 10.1089/dna.2020.5425] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Heat shock protein (HSP) is a family of highly conserved protein, which exists widely in various organisms and has a variety of important physiological functions. Currently, there is no systematic analysis of HSPs in human glioma. The aim of this study was to investigate the characteristics of HSPs through constructing protein-protein interaction network (PPIN) considering the expression level of HSPs in glioma. After the identification of the differentially expressed HSPs in glioma tissues, a specific PPIN was constructed and found that there were many interactions between the differentially expressed HSPs in glioma. Subcellular localization analysis shows that HSPs and their interacting proteins distribute from the cell membrane to the nucleus in a multilayer structure. By functional enrichment analysis, gene ontology analysis, and Kyoto Encyclopedia of Genes and Genomes pathway analysis, the potential function of HSPs and two meaningful enrichment pathways was revealed. In addition, nine HSPs (DNAJA4, DNAJC6, DNAJC12, HSPA6, HSP90B1, DNAJB1, DNAJB6, DNAJC10, and SERPINH1) are prognostic markers for human brain glioma. These analyses provide a full view of HSPs about their expression, biological process, as well as clinical significance in glioma.
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Affiliation(s)
- Hong Sun
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Hai-Ying Zou
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Xin-Yi Cai
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Hao-Feng Zhou
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Xiao-Qi Li
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Wei-Jie Xie
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Wen-Ming Xie
- Network and Information Center, Shantou University Medical College, Shantou, China
| | - Ze-Peng Du
- Department of Pathology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China
| | - Li-Yan Xu
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou, China
| | - En-Min Li
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Bing-Li Wu
- Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
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Wu X, Guo J, Chen Y, Liu X, Yang G, Wu Y, Tian Y, Liu N, Yang L, Wei S, Deng H, Chen W. The 60-kDa heat shock protein regulates energy rearrangement and protein synthesis to promote proliferation of multiple myeloma cells. Br J Haematol 2020; 190:741-752. [PMID: 32155663 DOI: 10.1111/bjh.16569] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/17/2020] [Indexed: 02/06/2023]
Abstract
To investigate the cellular mechanisms of multiple myeloma (MM), we used liquid chromatography-tandem mass spectrometry for proteomics analysis of CD138+ plasma cells from patients with MM and healthy controls. We found that the 60-kDa heat shock protein (HSP60, also known as HSPD1) was significantly upregulated in myeloma cells. HSP60 is an important chaperone protein that regulates the homeostasis of mitochondrial proteins and maintains mitochondrial function. Knockdown (KD) of HSP60 in myeloma cells resulted in inhibition of proliferation and reduced the quality of the mitochondria. Mitochondrial stress tests showed that HSP60 KD inhibited glycolysis and mitochondrial activity. Metabolomics showed a decrease in glycolysis and tricarboxylic acid cycle metabolites, and inhibited the formation of creatine and phosphocreatine by the reaction of S-adenosylmethionine (SAM) with amino acids mediated by demethyladenosine transferase 1, mitochondrial (TFB1M) and reduced energy storage substances. Moreover, HSP60 silencing influenced the synthesis of ribonucleotides and nicotinamide adenine dinucleotide phosphate (NADPH) by the pentose phosphate pathway to inhibit cell proliferation. HSP60 KD inhibited 5' adenosine monophosphate-activated protein kinase (AMPK), which inhibited the key enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), effecting the metabolism of fatty acids by inhibiting malonyl-coenzyme A. Our data suggest that reduced HSP60 expression alters metabolic reprogramming in MM, inhibits tumour progression and reduces mitochondrial-dependent biosynthesis, suggesting that HSP60 is a potential therapeutic target for MM treatment.
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Affiliation(s)
- Xiaoxiao Wu
- Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jianying Guo
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China
| | - Yuling Chen
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China
| | - Xiaohui Liu
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China
| | - Guangzhong Yang
- Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yin Wu
- Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Ying Tian
- Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Nian Liu
- Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Lin Yang
- Department of Hematology, The Second Hospital of Hebei medical University, Shi Jia Zhuang, China
| | - Songren Wei
- Department of Pharmacy, Foshan Maternal and Child Healthy Research Institute, Affiliated Hospital of Southern Medical University, Foshan, China
| | - Haiteng Deng
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China
| | - Wenming Chen
- Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
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Zhang R, Saredy J, Shao Y, Yao T, Liu L, Saaoud F, Yang WY, Sun Y, Johnson C, Drummer C, Fu H, Lu Y, Xu K, Liu M, Wang J, Cutler E, Yu D, Jiang X, Li Y, Li R, Wang L, Choi ET, Wang H, Yang X. End-stage renal disease is different from chronic kidney disease in upregulating ROS-modulated proinflammatory secretome in PBMCs - A novel multiple-hit model for disease progression. Redox Biol 2020; 34:101460. [PMID: 32179051 PMCID: PMC7327976 DOI: 10.1016/j.redox.2020.101460] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/28/2020] [Accepted: 02/07/2020] [Indexed: 12/17/2022] Open
Abstract
Background The molecular mechanisms underlying chronic kidney disease (CKD) transition to end-stage renal disease (ESRD) and CKD acceleration of cardiovascular and other tissue inflammations remain poorly determined. Methods We conducted a comprehensive data analyses on 7 microarray datasets in peripheral blood mononuclear cells (PBMCs) from patients with CKD and ESRD from NCBI-GEO databases, where we examined the expressions of 2641 secretome genes (SG). Results 1) 86.7% middle class (molecular weight >500 Daltons) uremic toxins (UTs) were encoded by SGs; 2) Upregulation of SGs in PBMCs in patients with ESRD (121 SGs) were significantly higher than that of CKD (44 SGs); 3) Transcriptomic analyses of PBMC secretome had advantages to identify more comprehensive secretome than conventional secretomic analyses; 4) ESRD-induced SGs had strong proinflammatory pathways; 5) Proinflammatory cytokines-based UTs such as IL-1β and IL-18 promoted ESRD modulation of SGs; 6) ESRD-upregulated co-stimulation receptors CD48 and CD58 increased secretomic upregulation in the PBMCs, which were magnified enormously in tissues; 7) M1-, and M2-macrophage polarization signals contributed to ESRD- and CKD-upregulated SGs; 8) ESRD- and CKD-upregulated SGs contained senescence-promoting regulators by upregulating proinflammatory IGFBP7 and downregulating anti-inflammatory TGF-β1 and telomere stabilizer SERPINE1/PAI-1; 9) ROS pathways played bigger roles in mediating ESRD-upregulated SGs (11.6%) than that in CKD-upregulated SGs (6.8%), and half of ESRD-upregulated SGs were ROS-independent. Conclusions Our analysis suggests novel secretomic upregulation in PBMCs of patients with CKD and ESRD, act synergistically with uremic toxins, to promote inflammation and potential disease progression. Our findings have provided novel insights on PBMC secretome upregulation to promote disease progression and may lead to the identification of new therapeutic targets for novel regimens for CKD, ESRD and their accelerated cardiovascular disease, other inflammations and cancers. (Total words: 279).
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Affiliation(s)
- Ruijing Zhang
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030013, China; Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
| | - Jason Saredy
- Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Ying Shao
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Tian Yao
- Shanxi Medical University, Taiyuan, Shanxi Province, 030001, China
| | - Lu Liu
- Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Fatma Saaoud
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | | | - Yu Sun
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Candice Johnson
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Charles Drummer
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Hangfei Fu
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Yifan Lu
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Keman Xu
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Ming Liu
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Shanxi Medical University, Taiyuan, Shanxi Province, 030001, China
| | - Jirong Wang
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Elizabeth Cutler
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; School of Science and Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Daohai Yu
- Department of Clinical Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Xiaohua Jiang
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Yafeng Li
- Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
| | - Rongshan Li
- Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
| | - Lihua Wang
- Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030013, China
| | - Eric T Choi
- Division of Vascular and Endovascular Surgery, Department of Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Hong Wang
- Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Xiaofeng Yang
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
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Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells. Int J Mol Sci 2020; 21:ijms21020661. [PMID: 31963896 PMCID: PMC7013437 DOI: 10.3390/ijms21020661] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 02/06/2023] Open
Abstract
The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial–mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents one of the main triggering agents for cell transformation. Curcumin is a natural compound with anti-inflammatory and anti-cancer properties with promising potential for the development of therapeutic drugs for the treatment of cancer as well as neurodegenerative diseases. Among the mediators of cancer development, HSP60 is a key factor for the maintenance of protein homeostasis and cell survival. High HSP60 levels were correlated, in particular, with cancer development and progression, and for this reason, we investigated the ability of curcumin to affect HSP60 expression, localization, and post-translational modifications using a neuroblastoma cell line. We have also looked at the ability of curcumin to interfere with the HSP60/HSP10 folding machinery. The cells were treated with 6, 12.5, and 25 µM of curcumin for 24 h, and the flow cytometry analysis showed that the compound induced apoptosis in a dose-dependent manner with a higher percentage of apoptotic cells at 25 µM. This dose of curcumin-induced a decrease in HSP60 protein levels and an upregulation of HSP60 mRNA expression. Moreover, 25 µM of curcumin reduced HSP60 ubiquitination and nitration, and the chaperonin levels were higher in the culture media compared with the untreated cells. Furthermore, curcumin at the same dose was able to favor HSP60 folding activity. The reduction of HSP60 levels, together with the increase in its folding activity and the secretion in the media led to the supposition that curcumin might interfere with cancer progression with a protective mechanism involving the chaperonin.
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Yun CW, Kim HJ, Lim JH, Lee SH. Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy. Cells 2019; 9:cells9010060. [PMID: 31878360 PMCID: PMC7017199 DOI: 10.3390/cells9010060] [Citation(s) in RCA: 180] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/06/2019] [Accepted: 12/21/2019] [Indexed: 12/24/2022] Open
Abstract
Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment.
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Affiliation(s)
- Chul Won Yun
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
| | - Hyung Joo Kim
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
| | - Ji Ho Lim
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
| | - Sang Hun Lee
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea; (C.W.Y.); (H.J.K.); (J.H.L.)
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31538, Korea
- Correspondence: ; Tel.: +82-02-709-2029
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Huang YH, Yeh CT. Functional Compartmentalization of HSP60-Survivin Interaction between Mitochondria and Cytosol in Cancer Cells. Cells 2019; 9:cells9010023. [PMID: 31861751 PMCID: PMC7016642 DOI: 10.3390/cells9010023] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/13/2019] [Accepted: 12/17/2019] [Indexed: 12/17/2022] Open
Abstract
Heat shock protein 60 (HSP60) and survivin reside in both the cytosolic and mitochondrial compartments under physiological conditions. They can form HSP60-survivin complexes through protein–protein interactions. Their expression levels in cancer tissues are positively correlated and higher expression of either protein is associated with poor clinical prognosis. The subcellular location of HSP60-survivin complex in either the cytosol or mitochondria is cell type-dependent, while the biological significance of HSP60-survivin interaction remains elusive. Current knowledge indicates that the function of HSP60 partly rests on where HSP60-survivin interaction takes place. HSP60 has a pro-survival function when binding to survivin in the mitochondria through interacting with other factors such as CCAR2 and p53. In response to cell death signals, mitochondrial survivin functions through preventing procaspase activation. Degradation of cytosolic survivin leads to the loss of mitochondrial membrane potential and aberrant mitosis processes. On the other hand, HSP60 release from mitochondria to cytosol upon death stimuli might exert a pro-death function, either through stabilizing Bax, enhancing procaspase-3 activation, or increasing protein ubiquitination. Combining the knowledge of mitochondrial HSP60-survivin complex function, cytosolic survivin degradation effect, and pro-death function upon mitochondria release of HSP60, a hypothetical scenario for HSP60-survivin shuttling upon death stimuli is proposed.
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Macario AJ, de Macario EC. Molecular mechanisms in chaperonopathies: clues to understanding the histopathological abnormalities and developing novel therapies. J Pathol 2019; 250:9-18. [PMID: 31579936 DOI: 10.1002/path.5349] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/02/2019] [Accepted: 09/17/2019] [Indexed: 12/13/2022]
Abstract
Molecular chaperones, many of which are heat shock proteins (Hsps), are components of the chaperoning system and when defective can cause disease, the chaperonopathies. Chaperone-gene variants cause genetic chaperonopathies, whereas in the acquired chaperonopathies the genes are normal, but their protein products are not, due to aberrant post-transcriptional mechanisms, e.g. post-translational modifications (PTMs). Since the chaperoning system is widespread in the body, chaperonopathies affect various tissues and organs, making these diseases of interest to a wide range of medical specialties. Genetic chaperonopathies are uncommon but the acquired ones are frequent, encompassing various types of cancer, and inflammatory and autoimmune disorders. The clinical picture of chaperonopathies is known. Much less is known on the impact that pathogenic mutations and PTMs have on the properties and functions of chaperone molecules. Elucidation of these molecular alterations is necessary for understanding the mechanisms underpinning the tissue and organ abnormalities occurring in patients. To illustrate this issue, we discuss structural-functional alterations caused by mutation in the chaperones CCT5 and HSPA9, and PTM effects on Hsp60. The data provide insights into what may happen when CCT5 and HSPA9 malfunction in patients, e.g. accumulation of cytotoxic protein aggregates with tissue destruction; or for Hsp60 with aberrant PTM, degradation and/or secretion of the chaperonin with mitochondrial damage. These and other possibilities are now open for investigation. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Alberto Jl Macario
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Columbus Center, Baltimore, MD, USA.,Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
| | - Everly Conway de Macario
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Columbus Center, Baltimore, MD, USA.,Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
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Iglesia RP, Fernandes CFDL, Coelho BP, Prado MB, Melo Escobar MI, Almeida GHDR, Lopes MH. Heat Shock Proteins in Glioblastoma Biology: Where Do We Stand? Int J Mol Sci 2019; 20:E5794. [PMID: 31752169 PMCID: PMC6888131 DOI: 10.3390/ijms20225794] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/15/2019] [Accepted: 11/16/2019] [Indexed: 12/16/2022] Open
Abstract
Heat shock proteins (HSPs) are evolutionary conserved proteins that work as molecular chaperones and perform broad and crucial roles in proteostasis, an important process to preserve the integrity of proteins in different cell types, in health and disease. Their function in cancer is an important aspect to be considered for a better understanding of disease development and progression. Glioblastoma (GBM) is the most frequent and lethal brain cancer, with no effective therapies. In recent years, HSPs have been considered as possible targets for GBM therapy due their importance in different mechanisms that govern GBM malignance. In this review, we address current evidence on the role of several HSPs in the biology of GBMs, and how these molecules have been considered in different treatments in the context of this disease, including their activities in glioblastoma stem-like cells (GSCs), a small subpopulation able to drive GBM growth. Additionally, we highlight recent works that approach other classes of chaperones, such as histone and mitochondrial chaperones, as important molecules for GBM aggressiveness. Herein, we provide new insights into how HSPs and their partners play pivotal roles in GBM biology and may open new therapeutic avenues for GBM based on proteostasis machinery.
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Affiliation(s)
| | | | | | | | | | | | - Marilene Hohmuth Lopes
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil; (R.P.I.); (C.F.d.L.F.); (B.P.C.); (M.B.P.); (M.I.M.E.); (G.H.D.R.A.)
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Hao Y, Wang W, Wu D, Liu K, Sun Y. Retracted: Bilobalide alleviates tumor necrosis factor‐alpha‐induced pancreatic beta‐cell MIN6 apoptosis and dysfunction through upregulation of miR‐153. Phytother Res 2019; 34:409-417. [PMID: 31667906 DOI: 10.1002/ptr.6533] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 09/22/2019] [Accepted: 10/09/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Yan Hao
- Department of EndocrinologyJining No.1 People's Hospital Jining China
| | - Weiwei Wang
- Department of EndocrinologyJining No.1 People's Hospital Jining China
| | - Dong Wu
- Emergency DepartmentJining No.1 People's Hospital Jining China
| | - Kai Liu
- Emergency DepartmentJinxiang People's Hospital Jining China
| | - Yihan Sun
- Department of EndocrinologyJining No.1 People's Hospital Jining China
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Guo J, Li X, Zhang W, Chen Y, Zhu S, Chen L, Xu R, Lv Y, Wu D, Guo M, Liu X, Lu W, Deng H. HSP60-regulated Mitochondrial Proteostasis and Protein Translation Promote Tumor Growth of Ovarian Cancer. Sci Rep 2019; 9:12628. [PMID: 31477750 PMCID: PMC6718431 DOI: 10.1038/s41598-019-48992-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/14/2019] [Indexed: 01/19/2023] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecological carcinoma due to the lack of diagnostic markers and effective drug targets. Discovery of new therapeutic targets in OC to improve the treatment outcome is urgently needed. We performed proteomic analysis of OC specimens and the paired normal tissues and revealed that proteins associated with mitochondrial proteostasis and protein translation were highly expressed in ovarian tumor tissues, indicating that mitochondria are required for tumor progression of OC. Heat shock protein 60 (HSP60), an important mitochondrial chaperone, was upregulated in ovarian tumors. HSP60 silencing significantly attenuated growth of OC cells in both cells and mice xenografts. Proteomic analysis revealed that HSP60 silencing downregulated proteins involved in mitochondrial functions and protein synthesis. Metabolomic analysis revealed that HSP60 silencing resulted in a more than 100-fold increase in cellular adenine levels, leading to increased adenosine monophosphate and an activated AMPK pathway, and consequently reduced mTORC1-mediated S6K and 4EBP1 phosphorylation to inhibit protein synthesis that suppressed the proliferation of OC cells. These results suggest that HSP60 knockdown breaks mitochondrial proteostasis, and inactivates the mTOR pathway to inhibit OC progression, suggesting that HSP60 is a potential therapeutic target for OC treatment.
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Affiliation(s)
- Jianying Guo
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Xiao Li
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, No.1 Xueshi Road, Hangzhou, Zhejiang, 310006, China
| | - Wenhao Zhang
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yuling Chen
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Songbiao Zhu
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Liang Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Beijing, 100037, PR China
| | - Renhua Xu
- School of Nursing, Binzhou Medical University, Yantai, 264003, China
| | - Yang Lv
- Department of Gastroenterology and Hepatology, and Center of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Di Wu
- Department of Gastroenterology and Hepatology, and Center of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, and Center of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Xiaohui Liu
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Weiguo Lu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, No.1 Xueshi Road, Hangzhou, Zhejiang, 310006, China.
| | - Haiteng Deng
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
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Kim EK, Lee SY, Kim Y, Ahn SM, Jang HH. Peroxiredoxin 1 post-transcriptionally regulates snoRNA expression. Free Radic Biol Med 2019; 141:1-9. [PMID: 31158443 DOI: 10.1016/j.freeradbiomed.2019.05.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/28/2019] [Accepted: 05/28/2019] [Indexed: 11/28/2022]
Abstract
Peroxiredoxin 1 (Prx1) is a member of the Prx family that detoxifies various peroxide substrates through conserved catalytic cysteine residues with the use of reducing equivalents. In addition to this well-known role of Prx1, we have previously demonstrated that Prx1 also has RNA-binding properties, but its function as an RNA-binding protein (RBP) remains unknown. To characterize the role of Prx1 as an RBP, we pulled down Prx1-RNA complexes and sequenced the target RNAs of Prx1. Through sequencing and further validation studies, we revealed that Prx1 binds to a specific subset of small nucleolar RNAs (snoRNAs) and regulates these molecules at the post-transcriptional level. We also found that active cysteine residues provide a structural and functional link between these two distinct functions of Prx1 (i.e., ROS scavenging and RNA-binding activities). Prx1 functions as a snoRNA-binding protein in its reduced state, and post-transcriptionally regulates the expression of a set of snoRNAs. However, when the active cysteine residues are oxidized, Prx1 loses its activity as a snoRNA-binding protein. This study is the first report describing the novel role of Prx1 as a post-transcriptional regulator of snoRNAs.
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Affiliation(s)
- Eun-Kyung Kim
- Department of Biochemistry, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea
| | - Sun Young Lee
- Center for Cancer Genome Discovery, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea
| | - Yosup Kim
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea
| | - Sung-Min Ahn
- Department of Genome Medicine and Science, College of Medicine, Gachon University, Incheon, 21936, Republic of Korea; Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, 21565, Republic of Korea.
| | - Ho Hee Jang
- Department of Biochemistry, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea; Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.
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