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Xiang L, Lou J, Zhao J, Geng Y, Zhang J, Wu Y, Zhao Y, Tao Z, Li Y, Qi J, Chen J, Yang L, Zhou K. Underlying Mechanism of Lysosomal Membrane Permeabilization in CNS Injury: A Literature Review. Mol Neurobiol 2025; 62:626-642. [PMID: 38888836 DOI: 10.1007/s12035-024-04290-6] [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: 01/27/2024] [Accepted: 06/06/2024] [Indexed: 06/20/2024]
Abstract
Lysosomes play a crucial role in various intracellular pathways as their final destination. Various stressors, whether mild or severe, can induce lysosomal membrane permeabilization (LMP), resulting in the release of lysosomal enzymes into the cytoplasm. LMP not only plays a pivotal role in various cellular events but also significantly contributes to programmed cell death (PCD). Previous research has demonstrated the participation of LMP in central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE). However, the mechanisms underlying LMP in CNS injuries are poorly understood. The occurrence of LMP leads to the activation of inflammatory pathways, increased levels of oxidative stress, and PCD. Herein, we present a comprehensive overview of the latest findings regarding LMP and highlight its functions in cellular events and PCDs (lysosome-dependent cell death, apoptosis, pyroptosis, ferroptosis, and autophagy). In addition, we consolidate the most recent insights into LMP in CNS injury by summarizing and exploring the latest advances. We also review potential therapeutic strategies that aim to preserve LMP or inhibit the release of enzymes from lysosomes to alleviate the consequences of LMP in CNS injury. A better understanding of the role that LMP plays in CNS injury may facilitate the development of strategic treatment options for CNS injury.
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Affiliation(s)
- Linyi Xiang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China
| | - Junsheng Lou
- Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jiayi Zhao
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China
| | - Yibo Geng
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China
| | - Jiacheng Zhang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China
| | - Yuzhe Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China
| | - Yinuo Zhao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Zhichao Tao
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China
| | - Yao Li
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China
| | - Jianjun Qi
- Department of Clinical Laboratory, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China.
| | - Jiaoxiang Chen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China.
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China.
| | - Liangliang Yang
- School of Pharmaceutical Sciences, Wenzhou Medical University, WenzhouZhejiang, 325035, China.
| | - Kailiang Zhou
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
- Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China.
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China.
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Rakib MRH, Messina V, Gargiulo JI, Lyons NA, Garcia SC. Graduate Student Literature Review: Potential use of HSP70 as an indicator of heat stress in dairy cows-A review. J Dairy Sci 2024; 107:11597-11610. [PMID: 39218068 DOI: 10.3168/jds.2024-24947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 07/16/2024] [Indexed: 09/04/2024]
Abstract
Heat stress (HS) poses significant challenges to the dairy industry, resulting in reduced milk production, impaired reproductive performance, and compromised animal welfare. Therefore, understanding the molecular mechanisms underlying cellular responses to HS is crucial for developing effective strategies to mitigate its adverse effects. Heat shock protein 70 (HSP70) has emerged as a potential player involved in cellular thermotolerance in dairy cows. This review provides a comprehensive overview of the role of HSP70 as a molecular chaperone in cellular thermotolerance in dairy cows under HS. HSP70 facilitates proper protein folding and prevents the aggregation of denatured proteins. By binding to misfolded proteins, it helps maintain protein homeostasis and prevents the accumulation of damaged proteins during HS. Additionally, HSP70 interacts with various regulatory proteins and signaling pathways, contributing to the cellular adaptive response to HS. The upregulation of HSP70 expression in response to HS is regulated by a complex network involving heat shock factors (HSF), heat shock element-binding proteins, and HSF co-chaperones. Therefore, HSP70 holds the potential to be a useful indicator of tissue stress due to its role in maintaining cellular balance and because it is released both inside and outside cells in response to stress. Traditional methods of measuring HSP70 in blood samples are labor intensive, and because the process is potentially stressful for the animals, this may subsequently affect the results. Therefore, measuring HSP expression in cow milk has shown promise as an easy, noninvasive, and accurate way to detect HS in dairy cows. Monitoring HSP70 levels in milk can be applied as a supplementary approach to identify HS or HS resistance of individual cows, select suitable animals, and guide targeted management strategies. However, despite the potential advantages of using HSP70 as a biomarker for monitoring HS on dairy cows, challenges remain in standardizing measurement protocols, establishing species-specific reference ranges, addressing interindividual variations, and determining the specificity of changes in HSP70 due to HS. Future research should focus on developing noninvasive techniques for HSP70 detection, with consideration of climatic conditions and unraveling the molecular interactions and regulatory networks involving HSP70.
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Affiliation(s)
- M R H Rakib
- Dairy Science Group, School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camden, NSW 2570, Australia; Bangladesh Livestock Research Institute, Savar, Dhaka 1341, Bangladesh.
| | - V Messina
- Dairy Science Group, School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camden, NSW 2570, Australia
| | - J I Gargiulo
- Dairy Science Group, School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camden, NSW 2570, Australia; NSW Department of Primary Industries and Regional Development, Menangle, NSW 2568, Australia
| | | | - S C Garcia
- Dairy Science Group, School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camden, NSW 2570, Australia
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Ghosh S, Vashisth K, Ghosh S, Han SS, Bhaskar R, Sinha JK. From sleep to cancer to neurodegenerative disease: the crucial role of Hsp70 in maintaining cellular homeostasis and potential therapeutic implications. J Biomol Struct Dyn 2024; 42:9812-9823. [PMID: 37643058 DOI: 10.1080/07391102.2023.2252509] [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: 04/02/2023] [Accepted: 08/20/2023] [Indexed: 08/31/2023]
Abstract
Sleep is a fundamental process essential for reparatory and restorative mechanisms in all organisms. Recent research has linked sleep to various pathological conditions, including cancer and neurodegeneration, which are associated with various molecular changes in different cellular environments. Despite the potential significance of various molecules, the HSPA1A or Hsp70 protein, which has possible connections with sleep and different neuropsychological and pathological disorders, has been explored the least. This paper explores the potential for manipulating and discovering drugs related to the Hsp70 protein to alleviate sleep problems and improve the prognosis for various other health issues. This paper discusses the critical role of Hsp70 in cancer, neurodegeneration, apoptosis, sleep, and its regulation at the structural level through allosteric mechanisms and different substrates. The significant impact of Hsp70's connection to various conditions suggests that existing sleep medicine could be used to improve such conditions, leading to improved outcomes, minimized research costs, and a new direction for current research. Overall, this paper highlights the potential of Hsp70 protein as a key therapeutic target for developing new drugs for the treatment of sleep disorders, cancer, neurodegeneration, and other related pathological conditions. Further research into the molecular mechanisms of Hsp70 regulation and its interactions with other cellular pathways is necessary to develop targeted treatments for these conditions.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Shampa Ghosh
- GloNeuro, Sector 107, Vishwakarma Road, Noida, India
- ICMR - National Institute of Nutrition, Tarnaka, Hyderabad, India
| | | | - Soumya Ghosh
- GloNeuro, Sector 107, Vishwakarma Road, Noida, India
| | - Sung Soo Han
- School of Chemical Engineering, Yeungnam University, Gyeonsang, Republic of Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Republic of Korea
| | - Rakesh Bhaskar
- School of Chemical Engineering, Yeungnam University, Gyeonsang, Republic of Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Republic of Korea
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Viana P, Hamar P. Targeting the heat shock response induced by modulated electro-hyperthermia (mEHT) in cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189069. [PMID: 38176599 DOI: 10.1016/j.bbcan.2023.189069] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/20/2023] [Accepted: 12/28/2023] [Indexed: 01/06/2024]
Abstract
The Heat Shock Response (HSR) is a cellular stress reaction crucial for cell survival against stressors, including heat, in both healthy and cancer cells. Modulated electro-hyperthermia (mEHT) is an emerging non-invasive cancer therapy utilizing electromagnetic fields to selectively target cancer cells via temperature-dependent and independent mechanisms. However, mEHT triggers HSR in treated cells. Despite demonstrated efficacy in cancer treatment, understanding the underlying molecular mechanisms for improved therapeutic outcomes remains a focus. This review examines the HSR induced by mEHT in cancer cells, discussing potential strategies to modulate it for enhanced tumor-killing effects. Approaches such as HSF1 gene-knockdown and small molecule inhibitors like KRIBB11 are explored to downregulate the HSR and augment tumor destruction. We emphasize the impact of HSR inhibition on cancer cell viability, mEHT sensitivity, and potential synergistic effects, addressing challenges and future directions. This understanding offers opportunities for optimizing treatment strategies and advancing precision medicine in cancer therapy.
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Affiliation(s)
- Pedro Viana
- Institute of Translational Medicine, Semmelweis University, Tűzoltó utca 37-49, 1094 Budapest, Hungary.
| | - Péter Hamar
- Institute of Translational Medicine, Semmelweis University, Tűzoltó utca 37-49, 1094 Budapest, Hungary.
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Xu L, Xiao S, Chai Z, Li T, Joon Lee J, Su G, Zhao Y. Study of novel ginsenoside metabolites targeting HSP70 as anti-prostate cancer drugs. Bioorg Chem 2024; 144:107131. [PMID: 38271824 DOI: 10.1016/j.bioorg.2024.107131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/30/2023] [Accepted: 01/11/2024] [Indexed: 01/27/2024]
Abstract
Ginsenoside 20 (R)-25-methoxy-dammarane-3 β, twelve β, 20 triol (AD-1) is a promising new drug for the treatment of prostate cancer, but its bioavailability is low. This study investigated the effects of the main metabolites PD and M6 of AD-1 on prostate cancer cell PC3. The in vitro experimental results showed that the IC50 values of PC3 cells treated with PD and M6 were 65.61 and 11.72, respectively. Both PD and M6 inhibited the migration of PC3 cells, and the cell cycle was blocked in the G1 phase. The apoptosis rates of cells following M6 treatment at concentrations of 7.5, 15, and 30 μM were 13.4 %, 17.5 %, and 41.4 %, respectively, which stimulated the expression of apoptosis protein and significantly increased intracellular ROS levels. In xenograft models, PD and M6 have been reported to significantly inhibit tumor growth. We used a genome-wide mRNA expression profile to study the effects of PD and M6 on gene expression in PC3 cancer cells. PD and M6 induced downregulation of HSP70 subtypes HSPA1A and HSPA1B. RT-PCR confirmed that the significant down-regulation of HSP70 subtype expressions was consistent with the results of Transcriptome analysis. Moreover, M6 significantly downregulated the expression of AR, which was further proved by Western blot analysis. In summary, our research findings provide a scientific basis for interpreting the significant activity of AD-1 in prostate cancer, and for the research and development of PD and M6 as novel HSP70 inhibitors.
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Affiliation(s)
- Lei Xu
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, China; Shanxi University of Chinese Medicine, Jinzhong 030619, China
| | - Shengnan Xiao
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, China; Shanxi University of Chinese Medicine, Jinzhong 030619, China
| | - Zhi Chai
- Shanxi University of Chinese Medicine, Jinzhong 030619, China
| | - Tao Li
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, China
| | - Jung Joon Lee
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, China
| | - Guangyue Su
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Yuqing Zhao
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, China.
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Koh M, Lim H, Jin H, Kim M, Hong Y, Hwang YK, Woo Y, Kim ES, Kim SY, Kim KM, Lim HK, Jung J, Kang S, Park B, Lee HB, Han W, Lee MS, Moon A. ANXA2 (annexin A2) is crucial to ATG7-mediated autophagy, leading to tumor aggressiveness in triple-negative breast cancer cells. Autophagy 2024; 20:659-674. [PMID: 38290972 PMCID: PMC10936647 DOI: 10.1080/15548627.2024.2305063] [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: 04/14/2023] [Revised: 12/27/2023] [Accepted: 12/29/2023] [Indexed: 02/01/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is associated with a poor prognosis and metastatic growth. TNBC cells frequently undergo macroautophagy/autophagy, contributing to tumor progression and chemotherapeutic resistance. ANXA2 (annexin A2), a potential therapeutic target for TNBC, has been reported to stimulate autophagy. In this study, we investigated the role of ANXA2 in autophagic processes in TNBC cells. TNBC patients exhibited high levels of ANXA2, which correlated with poor outcomes. ANXA2 increased LC3B-II levels following bafilomycin A1 treatment and enhanced autophagic flux in TNBC cells. Notably, ANXA2 upregulated the phosphorylation of HSF1 (heat shock transcription factor 1), resulting in the transcriptional activation of ATG7 (autophagy related 7). The mechanistic target of rapamycin kinase complex 2 (MTORC2) played an important role in ANXA2-mediated ATG7 transcription by HSF1. MTORC2 did not affect the mRNA level of ANXA2, but it was involved in the protein stability of ANXA2. HSPA (heat shock protein family A (Hsp70)) was a potential interacting protein with ANXA2, which may protect ANXA2 from lysosomal proteolysis. ANXA2 knockdown significantly increased sensitivity to doxorubicin, the first-line chemotherapeutic regimen for TNBC treatment, suggesting that the inhibition of autophagy by ANXA2 knockdown may overcome doxorubicin resistance. In a TNBC xenograft mouse model, we demonstrated that ANXA2 knockdown combined with doxorubicin administration significantly inhibited tumor growth compared to doxorubicin treatment alone, offering a promising avenue to enhance the effectiveness of chemotherapy. In summary, our study elucidated the molecular mechanism by which ANXA2 modulates autophagy, suggesting a potential therapeutic approach for TNBC treatment.Abbreviation: ATG: autophagy related; ChIP: chromatin-immunoprecipitation; HBSS: Hanks' balanced salt solution; HSF1: heat shock transcription factor 1; MTOR: mechanistic target of rapamycin kinase; TNBC: triple-negative breast cancer; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3.
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Affiliation(s)
- Minsoo Koh
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Hyesol Lim
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Hao Jin
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Minjoo Kim
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Yeji Hong
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Young Keun Hwang
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Yunjung Woo
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Eun-Sook Kim
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Sun Young Kim
- Department of Chemistry, College of Science and Technology, Duksung Women’s University, Seoul, Korea
| | - Kyung Mee Kim
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Hyun Kyung Lim
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Joohee Jung
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
| | - Sujin Kang
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Boyoun Park
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Han-Byoel Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Wonshik Han
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Myung-Shik Lee
- Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea
| | - Aree Moon
- Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea
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Liang K, Sun Y, Xie L, Liu Y, You Y, Xu J, Ma F, Huang Y, Song Q, Xiao W, Huang J, Gao X, Chen J. Biologically Self-Assembled Tumor Cell-Derived Cancer Nanovaccines as an All-in-One Platform for Cancer Immunotherapy. ACS NANO 2024; 18:6702-6717. [PMID: 38359389 DOI: 10.1021/acsnano.4c01050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Tumor cell-derived cancer nanovaccines introduce tumor cell-derived components as functional units that endow the nanovaccine systems with some advantages, especially providing all potential tumor antigens. However, cumbersome assembly steps, potential risks of exogenous adjuvants, as well as insufficient lymph node (LN) targeting and dendritic cell (DC) internalization limit the efficacy and clinical translation of existing tumor cell-derived cancer nanovaccines. Herein, we introduced an endoplasmic reticulum (ER) stress inducer α-mangostin (αM) into tumor cells through poly(d, l-lactide-co-glycolide) nanoparticles and harvested biologically self-assembled tumor cell-derived cancer nanovaccines (αM-Exos) based on the biological process of tumor cell exocytosing nanoparticles through tumor-derived exosomes (TEXs). Besides presenting multiple potential antigens, αM-Exos inherited abundant 70 kDa heat shock proteins (Hsp70s) upregulated by ER stress, which can not only act as endogenous adjuvants but also improve LN targeting and DC internalization. Following subcutaneous injection, αM-Exos efficiently migrated to LNs and was expeditiously endocytosed by DCs, delivering tumor antigens and adjuvants to DCs synchronously, which then powerfully triggered antitumor immune responses and established long-term immune memory. Our study exhibited an all-in-one biologically self-assembled tumor cell-derived cancer nanovaccine platform, and the fully featured cancer nanovaccines assembled efficiently through this platform are promising for desirable cancer immunotherapy.
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Affiliation(s)
- Kaifan Liang
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China
| | - Yinzhe Sun
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China
| | - Laozhi Xie
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China
| | - Yipu Liu
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China
| | - Yang You
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China
| | - Jianpei Xu
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China
| | - Fenfen Ma
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China
| | - Yukun Huang
- Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China
| | - Qingxiang Song
- Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China
| | - Wenze Xiao
- Department of Rheumatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 201399, Shanghai, China
| | - Jianming Huang
- School of Pharmacy, Fudan University, 201203 Shanghai, China
| | - Xiaoling Gao
- Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China
| | - Jun Chen
- Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China
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Martin-Folgar R, Sabroso C, Cañas-Portilla AI, Torres-Ruíz M, González-Caballero MC, Dorado H, Velasco I, Morales M. DNA damage and molecular level effects induced by polystyrene (PS) nanoplastics (NPs) after Chironomus riparius (Diptera) larvae. CHEMOSPHERE 2024; 346:140552. [PMID: 37914044 DOI: 10.1016/j.chemosphere.2023.140552] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 11/03/2023]
Abstract
In this work, we analyzed the early molecular effects of polystyrene (PS) nanoplastics (NPs) on an aquatic primary consumer (larvae of Chironomus riparius, Diptera) to evaluate their potential DNA damage and the transcriptional response of different genes related to cellular and oxidative stress, endocrine response, developmental, oxygen transport, and immune response. After 24-h exposures of larvae to doses of PS NPs close to those currently found in the environment, the results revealed a large genotoxic effect. This end was evidenced after significant increases in DNA strand breaks of C. riparius larvae quantified by the comet assay, together with results obtained when analyzing the expression of four genes involved in DNA repair (xrrc1, ATM, DECAY and NLK) and which were reduced in the presence of these nanomaterials. Consequently, this reduction trend is likely to prevent the repair of DNA damage caused by PS NPs. In addition, the same tendency to reduce the expression of genes involved in cellular stress, oxidative stress, ecdysone pathway, development, and oxygen transport was observed. Taken together, these results suggest that PS NPs reduce the expression of hormonal target genes and a developmental gene. We show, for the first time, effects of PS NPs on the endocrine system of C. riparius and suggest a possible mechanism of blocking ecdysteroid hormones in insects. Moreover, the NPs were able to inhibit the expression of hemoglobin (Hb C), a protein involved in oxygen transport, and activate a gene of the humoral immune system. These data reveal for the first time the genomic effects of PS NPs in the aquatic invertebrate C. riparius, at the base of the food chain.
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Affiliation(s)
- Raquel Martin-Folgar
- Grupo de Biología y Toxicología Ambiental, Departamento de Física Matemática y de Fluidos, Facultad de Ciencias, UNED, Avda. Esparta s/n Las Rozas, (Madrid), Spain.
| | - Celia Sabroso
- Grupo de Biología y Toxicología Ambiental, Departamento de Física Matemática y de Fluidos, Facultad de Ciencias, UNED, Avda. Esparta s/n Las Rozas, (Madrid), Spain
| | - Ana I Cañas-Portilla
- Environmental Toxicology Unit, Centro Nacional de Sanidad Ambiental (CNSA), Instituto de Salud Carlos III (ISCIII), Ctra. Majadahonda-Pozuelo Km. 2,2., 28220, Majadahonda, (Madrid), Spain
| | - Mónica Torres-Ruíz
- Environmental Toxicology Unit, Centro Nacional de Sanidad Ambiental (CNSA), Instituto de Salud Carlos III (ISCIII), Ctra. Majadahonda-Pozuelo Km. 2,2., 28220, Majadahonda, (Madrid), Spain
| | - Mª Carmen González-Caballero
- Environmental Toxicology Unit, Centro Nacional de Sanidad Ambiental (CNSA), Instituto de Salud Carlos III (ISCIII), Ctra. Majadahonda-Pozuelo Km. 2,2., 28220, Majadahonda, (Madrid), Spain
| | - Helena Dorado
- Grupo de Biología y Toxicología Ambiental, Departamento de Física Matemática y de Fluidos, Facultad de Ciencias, UNED, Avda. Esparta s/n Las Rozas, (Madrid), Spain
| | - Ignacio Velasco
- Grupo de Biología y Toxicología Ambiental, Departamento de Física Matemática y de Fluidos, Facultad de Ciencias, UNED, Avda. Esparta s/n Las Rozas, (Madrid), Spain
| | - Mónica Morales
- Grupo de Biología y Toxicología Ambiental, Departamento de Física Matemática y de Fluidos, Facultad de Ciencias, UNED, Avda. Esparta s/n Las Rozas, (Madrid), Spain.
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Sannino S, Manuel AM, Shang C, Wendell SG, Wipf P, Brodsky JL. Non-Essential Amino Acid Availability Influences Proteostasis and Breast Cancer Cell Survival During Proteotoxic Stress. Mol Cancer Res 2023; 21:675-690. [PMID: 36961392 PMCID: PMC10330057 DOI: 10.1158/1541-7786.mcr-22-0843] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 02/11/2023] [Accepted: 03/21/2023] [Indexed: 03/25/2023]
Abstract
Protein homeostasis (proteostasis) regulates tumor growth and proliferation when cells are exposed to proteotoxic stress, such as during treatment with certain chemotherapeutics. Consequently, cancer cells depend to a greater extent on stress signaling, and require the integrated stress response (ISR), amino acid metabolism, and efficient protein folding and degradation pathways to survive. To define how these interconnected pathways are wired when cancer cells are challenged with proteotoxic stress, we investigated how amino acid abundance influences cell survival when Hsp70, a master proteostasis regulator, is inhibited. We previously demonstrated that cancer cells exposed to a specific Hsp70 inhibitor induce the ISR via the action of two sensors, GCN2 and PERK, in stress-resistant and sensitive cells, respectively. In resistant cells, the induction of GCN2 and autophagy supported resistant cell survival, yet the mechanism by which these events were induced remained unclear. We now report that amino acid availability reconfigures the proteostasis network. Amino acid supplementation, and in particular arginine addition, triggered cancer cell death by blocking autophagy. Consistent with the importance of amino acid availability, which when limited activates GCN2, resistant cancer cells succumbed when challenged with a potentiator for another amino acid sensor, mTORC1, in conjunction with Hsp70 inhibition. IMPLICATIONS These data position amino acid abundance, GCN2, mTORC1, and autophagy as integrated therapeutic targets whose coordinated modulation regulates the survival of proteotoxic-resistant breast cancer cells.
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Affiliation(s)
- Sara Sannino
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Allison M. Manuel
- Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA
- Mass Spectrometry and Proteomics Core, The University of Utah, Salt Lake City, UT, USA
| | - Chaowei Shang
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Stacy G. Wendell
- Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology University of Pittsburgh, Pittsburgh, PA, USA
| | - Peter Wipf
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jeffrey L Brodsky
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
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10
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Ajmal MR. Protein Misfolding and Aggregation in Proteinopathies: Causes, Mechanism and Cellular Response. Diseases 2023; 11:30. [PMID: 36810544 PMCID: PMC9944956 DOI: 10.3390/diseases11010030] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/02/2023] [Accepted: 02/05/2023] [Indexed: 02/11/2023] Open
Abstract
Proteins are central to life functions. Alterations in the structure of proteins are reflected in their function. Misfolded proteins and their aggregates present a significant risk to the cell. Cells have a diverse but integrated network of protection mechanisms. Streams of misfolded proteins that cells are continuously exposed to must be continually monitored by an elaborated network of molecular chaperones and protein degradation factors to control and contain protein misfolding problems. Aggregation inhibition properties of small molecules such as polyphenols are important as they possess other beneficial properties such as antioxidative, anti-inflammatory, and pro-autophagic properties and help neuroprotection. A candidate with such desired features is important for any possible treatment development for protein aggregation diseases. There is a need to study the protein misfolding phenomenon so that we can treat some of the worst kinds of human ailments related to protein misfolding and aggregation.
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Affiliation(s)
- Mohammad Rehan Ajmal
- Physical Biochemistry Research Laboratory, Biochemistry Department, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia
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11
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Abd El-Fadeal NM, Ellawindy A, Jeraiby MA, Qusti SY, Alshammari EM, Alzahrani AK, Ismail EA, Ehab Z, Toraih EA, Fawzy MS, Mohamed MH. HSP70 Expression Signature in Renal Cell Carcinoma: A Clinical and Bioinformatic Analysis Approach. Genes (Basel) 2023; 14:genes14020355. [PMID: 36833281 PMCID: PMC9957082 DOI: 10.3390/genes14020355] [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: 12/03/2022] [Revised: 01/18/2023] [Accepted: 01/23/2023] [Indexed: 01/31/2023] Open
Abstract
Heat shock proteins (HSPs) are cytoprotective against stressful conditions, as in the case of cancer cell metabolism. Scientists proposed that HSP70 might be implicated in increased cancer cell survival. This study aimed to investigate the HSP70 (HSPA4) gene expression signature in patients with renal cell carcinoma (RCC) in correlation to cancer subtype, stage, grade, and recurrence, combining both clinicopathological and in silico analysis approaches. One hundred and thirty archived formalin-fixed paraffin-embedded samples, including 65 RCC tissue specimens and their paired non-cancerous tissues, were included in the study. Total RNA was extracted from each sample and analyzed using TaqMan quantitative Real-Time Polymerase Chain Reaction. Correlation and validation to the available clinicopathological data and results were executed. Upregulated HSP70 (HSPA4) gene expression was evident in RCC compared to non-cancer tissues in the studied cohort and was validated by in silico analysis. Furthermore, HSP70 expression levels showed significant positive correlations with cancer size, grade, and capsule infiltration, as well as recurrence in RCC patients. The expression levels negatively correlated with the overall survival (r = -0.87, p < 0.001). Kaplan-Meier curves showed lower survival rates in high HSP70 expressor group compared to the low expressors. In conclusion, the HSP70 expression levels are associated with poor RCC prognosis in terms of advanced grade, capsule infiltration, recurrence, and short survival.
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Affiliation(s)
- Noha M. Abd El-Fadeal
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Center of Excellence in Molecular and Cellular Medicine, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Oncology Diagnostic Unit, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Alia Ellawindy
- Medical Genetics Unit, Department of Histology and Cell Biology, Suez Canal University, Ismailia 41522, Egypt
| | - Mohammed A. Jeraiby
- Department of Biochemistry, Faculty of Medicine, Jazan University, Jazan 82621, Saudi Arabia
| | - Safaa Y. Qusti
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Eida M. Alshammari
- Department of Chemistry, College of Sciences, University of Ha’il, Ha’il 2440, Saudi Arabia
| | - Ahmad Khuzaim Alzahrani
- Medical Laboratory Technology, Faculty of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia
| | - Ezzat A. Ismail
- Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Ziad Ehab
- Faculty of Medicine, Mansoura University, Mansoura 21955, Egypt
| | - Eman A. Toraih
- Medical Genetics Unit, Department of Histology and Cell Biology, Suez Canal University, Ismailia 41522, Egypt
- Division of Endocrine and Oncologic Surgery, Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Correspondence: (E.A.T.); (M.S.F.)
| | - Manal S. Fawzy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar 1321, Saudi Arabia
- Correspondence: (E.A.T.); (M.S.F.)
| | - Marwa Hussein Mohamed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
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Abstract
The Hsp70/Hsp90 organising protein (Hop, also known as stress-inducible protein 1/STI1/STIP1) has received considerable attention for diverse cellular functions in both healthy and diseased states. There is extensive evidence that intracellular Hop is a co-chaperone of the major chaperones Hsp70 and Hsp90, playing an important role in the productive folding of Hsp90 client proteins, although recent evidence suggests that eukaryotic Hop is regulatory within chaperone complexes rather than essential. Consequently, Hop is implicated in many key signalling pathways, including aberrant pathways leading to cancer. Hop is also secreted, and it is now well established that Hop interacts with the prion protein, PrPC, to mediate multiple signalling events. The intracellular and extracellular forms of Hop most likely represent two different isoforms, although the molecular determinants of these divergent functions are yet to be identified. There is also a growing body of research that reports the involvement of Hop in cellular activities that appear independent of either chaperones or PrPC. While the various cellular functions of Hop have been described, its biological function remains elusive. However, recent knockout studies in mammals suggest that Hop has an important role in embryonic development. This review provides a critical overview of the latest molecular, cellular and biological research on Hop, critically evaluating its function in healthy systems and how this function is adapted in diseased states.
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13
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Abstract
Molecular chaperones and co-chaperones facilitate the assembly of newly synthesized polypeptides and refolding of unfolded or misfolded proteins, thereby maintaining protein homeostasis in cells. As co-chaperones of the master chaperone heat shock protein (HSP) 70, the HSP40 (DNAJ) proteins are largest chaperone family in eukaryotic cells. They contain a characteristic J-domain which mediates interaction with HSP70, thereby helping protein folding. It is well perceived that protein homeostasis is vital for neuronal health. DNAJ family proteins have been linked to the occurrence and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, Charcot-Marie-Tooth disease, spinal muscular atrophy, distal hereditary motor neuropathy, limb-girdle type muscular dystrophy, neuronal ceroid lipofuscinosis and essential tremor in recent studies. DNAJA1 effectively degrades huntington aggregates; DNAJB1 can degrade protein aggregates ataxin-3; DNAJB2 can inhibit the formation of huntington aggregates; DNAJB6 can inhibit the aggregation of Aβ 42 and α-synuclein; DNAJC5 can promote the release of TDP-43, τ protein, and α-synuclein into the extracellular space. Mutations in the essential tremor-associated DNAJC13 gene can prevent endosome protein trafficking. This article reviews the mechanism of DNAJ protein family in neurodegenerative diseases.
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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: 206] [Impact Index Per Article: 68.7] [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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15
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Expression and bioinformatics analyses show HSP70 complements BCL2 action in oral carcinogenesis. J Oral Biol Craniofac Res 2022; 12:599-603. [DOI: 10.1016/j.jobcr.2022.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 06/01/2022] [Accepted: 07/16/2022] [Indexed: 11/23/2022] Open
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16
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Almuslehi MSM, Sen MK, Shortland PJ, Mahns DA, Coorssen JR. Histological and Top-Down Proteomic Analyses of the Visual Pathway in the Cuprizone Demyelination Model. J Mol Neurosci 2022; 72:1374-1401. [PMID: 35644788 PMCID: PMC9170674 DOI: 10.1007/s12031-022-01997-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 03/07/2022] [Indexed: 10/27/2022]
Abstract
Abstract
A change in visual perception is a frequent early symptom of multiple sclerosis (MS), the pathoaetiology of which remains unclear. Following a slow demyelination process caused by 12 weeks of low-dose (0.1%) cuprizone (CPZ) consumption, histology and proteomics were used to investigate components of the visual pathway in young adult mice. Histological investigation did not identify demyelination or gliosis in the optic tracts, pretectal nuclei, superior colliculi, lateral geniculate nuclei or visual cortices. However, top-down proteomic assessment of the optic nerve/tract revealed a significant change in the abundance of 34 spots in high-resolution two-dimensional (2D) gels. Subsequent liquid chromatography-tandem mass spectrometry (LC-TMS) analysis identified alterations in 75 proteoforms. Literature mining revealed the relevance of these proteoforms in terms of proteins previously implicated in animal models, eye diseases and human MS. Importantly, 24 proteoforms were not previously described in any animal models of MS, eye diseases or MS itself. Bioinformatic analysis indicated involvement of these proteoforms in cytoskeleton organization, metabolic dysregulation, protein aggregation and axonal support. Collectively, these results indicate that continuous CPZ-feeding, which evokes a slow demyelination, results in proteomic changes that precede any clear histological changes in the visual pathway and that these proteoforms may be potential early markers of degenerative demyelinating conditions.
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17
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Cytoplasmic proteotoxicity regulates HRI-dependent phosphorylation of eIF2α via the Hsp70-Bag3 module. iScience 2022; 25:104282. [PMID: 35573186 PMCID: PMC9097715 DOI: 10.1016/j.isci.2022.104282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/27/2022] [Accepted: 04/19/2022] [Indexed: 11/30/2022] Open
Abstract
The major heat shock protein Hsp70 forms a complex with a scaffold protein Bag3 that links it to components of signaling pathways. Via these interactions, the Hsp70-Bag3 module functions as a proteotoxicity sensor that controls cell signaling. Here, to search for pathways regulated by the complex, we utilized JG-98, an allosteric inhibitor of Hsp70 that blocks its interaction with Bag3. RNAseq followed by the pathway analysis indicated that several signaling pathways including UPR were activated by JG-98. Surprisingly, only the eIF2α-associated branch of the UPR was activated, while other UPR branches were not induced, suggesting that the response was unrelated to the ER proteotoxicity and ER-associated kinase PERK1. Indeed, induction of the UPR genes under these conditions was driven by a distinct eIF2α kinase HRI. Hsp70-Bag3 directly interacted with HRI and regulated eIF2α phosphorylation upon cytoplasmic proteotoxicity. Therefore, cytosolic proteotoxicity can activate certain UPR genes via Hsp70-Bag3-HRI-eIF2α axis.
Disruption of Hsp70-Bag3 module activates the unfolded protein response (UPR) This induction of UPR genes is mediated by HRI-dependent phosphorylation of eIF2α Hsp70-Bag3 “monitors” cytoplasmic proteotoxicity to activate the HRI-eIF2α axis eIF2α integrates proteotoxicity signals from ER and cytoplasm
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18
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Rare β-Resorcylic Acid Derivatives from a Halophyte-Associated Fungus Colletotrichum gloeosporioides JS0419 and Their Antifungal Activities. Mar Drugs 2022; 20:md20030195. [PMID: 35323494 PMCID: PMC8951769 DOI: 10.3390/md20030195] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 03/05/2022] [Accepted: 03/06/2022] [Indexed: 02/04/2023] Open
Abstract
Six new β-resorcylic acid derivatives (1–5 and 7) were isolated from a halophyte-associated fungus, Colletotrichum gloeosporioides JS0419, together with four previously reported β-resorcylic acid lactones (RALs). The relative and absolute stereochemistry of 1 was completely established by a combination of spectroscopic data and chemical reactions. The structures of the isolated compounds were elucidated by analysis of HRMS and NMR data. Notably, compounds 1–3 had a β-resorcylic acid harboring a long unesterified aliphatic side chain, whereas the long aliphatic chains were esterified to form macrolactones in 4–9. Among the isolated compounds, monocillin I and radicicol showed potent antifungal activities against Cryptococcus neoformans, comparable to clinically available antifungal agents and radicicol showed weak antifungal activity against Candida albicans. These findings provide insight into the chemical diversity of fungal RAL-type compounds and their pharmacological potential.
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19
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20
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Brakel A, Kolano L, Kraus CN, Otvos L, Hoffmann R. Functional Effects of ARV-1502 Analogs Against Bacterial Hsp70 and Implications for Antimicrobial Activity. Front Chem 2022; 10:798006. [PMID: 35223768 PMCID: PMC8864165 DOI: 10.3389/fchem.2022.798006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/11/2022] [Indexed: 01/19/2023] Open
Abstract
The antimicrobial peptide (AMP) ARV-1502 was designed based on naturally occurring short proline-rich AMPs, including pyrrhocoricin and drosocin. Identification of chaperone DnaK as a therapeutic target in Escherichia coli triggered intense research on the ligand-DnaK-interactions using fluorescence polarization and X-ray crystallography to reveal the binding motif and characterize the influence of the chaperone on protein refolding activity, especially in stress situations. In continuation of this research, 182 analogs of ARV-1502 were designed by substituting residues involved in antimicrobial activity against Gram-negative pathogens. The peptides synthesized on solid-phase were examined for their binding to E. coli and S. aureus DnaK providing 15 analogs with improved binding characteristics for at least one DnaK. These 15 analogs were distinguished from the original sequence by their increased hydrophobicity parameters. Additionally, the influence of the entire DnaK chaperone system, including co-chaperones DnaJ and GrpE on refolding and ATPase activity, was investigated. The increasingly hydrophobic peptides showed a stronger inhibitory effect on the refolding activity of E. coli chaperones, reducing protein refolding by up to 64%. However, these more hydrophobic peptides had only a minor effect on the ATPase activity. The most dramatic changes on the ATPase activity involved peptides with aspartate substitutions. Interestingly, these peptides resulted in a 59% reduction of the ATPase activity in the E. coli chaperone system whereas they stimulated the ATPase activity in the S. aureus system up to 220%. Of particular note is the improvement of the antimicrobial activity against S. aureus from originally >128 µg/mL to as low as 16 µg/mL. Only a single analog exhibited improved activity over the original value of 8 µg/mL against E. coli. Overall, the various moderate-throughput screenings established here allowed identifying (un)favored substitutions on 1) DnaK binding, 2) the ATPase activity of DnaK, 3) the refolding activity of DnaK alone or together with co-chaperones, and 4) the antimicrobial activity against both E. coli and S. aureus.
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Affiliation(s)
- Alexandra Brakel
- Faculty of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Universität Leipzig, Leipzig, Germany
- Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany
- *Correspondence: Alexandra Brakel, ; Ralf Hoffmann,
| | - Lisa Kolano
- Faculty of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Universität Leipzig, Leipzig, Germany
- Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany
| | | | - Laszlo Otvos
- Aceragen, Inc., Durham, NC, United States
- Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary
| | - Ralf Hoffmann
- Faculty of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Universität Leipzig, Leipzig, Germany
- Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany
- *Correspondence: Alexandra Brakel, ; Ralf Hoffmann,
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21
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Abou Zeid LY, Shanmugapriya S, Rumney RL, Mosser DD. Caspase-mediated cleavage of miRNA processing proteins Drosha, DGCR8, Dicer, and TRBP2 in heat-shocked cells and its inhibition by HSP70 overexpression. Cell Stress Chaperones 2022; 27:11-25. [PMID: 34719748 PMCID: PMC8821752 DOI: 10.1007/s12192-021-01242-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/21/2021] [Accepted: 10/01/2021] [Indexed: 10/19/2022] Open
Abstract
Cells respond to stress through adaptive mechanisms that limit cellular damage and prevent cell death. MicroRNAs act as regulators of stress responses and stress can impact the functioning of miRNA biogenesis pathways. We were interested in the effect that severe proteotoxic stress capable of inducing apoptosis may have on miRNA biogenesis and the impact of the molecular chaperone protein HSP70 under these conditions. We found that the miRNA processing enzymes Drosha and Dicer and their accessory proteins DGCR8 and TRBP2 are cleaved by caspases in apoptotic cells. Overexpression of HSP70 prevented caspase activation and the degradation of these processing proteins. Caspase cleavage of TRBP2 was mapped to amino acid 234 which separates the two dsRNA-binding domains from the C-terminal Dicer interacting domain. Overexpression of TRBP2 was found to increase miRNA maturation, while expression of either of the fragments generated by caspase cleavage impaired maturation. These results indicate that inactivation of miRNA biogenesis is a critical feature of apoptosis and that cleavage of TRBP2, rather than simply a loss of function, serves to create positive acting inhibitors of pre-miRNA maturation.
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Affiliation(s)
- Lina Y Abou Zeid
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada
| | | | - Rebecca L Rumney
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada
| | - Dick D Mosser
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada.
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22
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HSP90 as a regulator of extracellular matrix dynamics. Biochem Soc Trans 2021; 49:2611-2625. [PMID: 34913470 DOI: 10.1042/bst20210374] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/25/2021] [Accepted: 11/30/2021] [Indexed: 01/03/2023]
Abstract
The extracellular matrix (ECM) is a dynamic and organised extracellular network assembled from proteins and carbohydrates exported from the cell. The ECM is critical for multicellular life, providing spatial and temporal cellular cues to maintain tissue homeostasis. Consequently, ECM production must be carefully balanced with turnover to ensure homeostasis; ECM dysfunction culminates in disease. Hsp90 is a molecular chaperone central to protein homeostasis, including in the ECM. Intracellular and extracellular Hsp90 isoforms collaborate to regulate the levels and status of proteins in the ECM via multiple mechanisms. In so doing, Hsp90 regulates ECM dynamics, and changes in Hsp90 levels or activity support the development of ECM-related diseases, like cancer and fibrosis. Consequently, Hsp90 levels may have prognostic value, while inhibition of Hsp90 may have therapeutic potential in conditions characterised by ECM dysfunction.
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23
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Lu J, Zhao Y, Liu M, Lu J, Guan S. Toward improved human health: Nrf2 plays a critical role in regulating ferroptosis. Food Funct 2021; 12:9583-9606. [PMID: 34542140 DOI: 10.1039/d1fo01036k] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ferroptosis is a recently defined type of regulated cell death caused by an excess iron-dependent accumulation of lipid peroxides and is morphologically and biochemically distinct from other types of cell death. Notably, Nrf2 is identified to exquisitely modulate ferroptosis due to its ability to target a host of ferroptosis cascade genes, which places Nrf2 in the pivotal position of ferroptosis. This paper reviews the regulation effect of Nrf2 on ferroptosis, different activation mechanisms of Nrf2 as well as the relevance of the Nrf2-ferroptosis axis in diseases, and finally summarizes foods with beneficial effects in ferroptosis via the Nrf2 pathway and aims to serve as a reference for follow-up studies of food functions related to Nrf2, ferroptosis, and human health.
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Affiliation(s)
- Jing Lu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China. .,Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Yanan Zhao
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
| | - Meitong Liu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
| | - Jianing Lu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
| | - Shuang Guan
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China. .,Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, People's Republic of China
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Mabanglo MF, Bhandari V, Houry WA. Substrates and interactors of the ClpP protease in the mitochondria. Curr Opin Chem Biol 2021; 66:102078. [PMID: 34446368 DOI: 10.1016/j.cbpa.2021.07.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 12/21/2022]
Abstract
The ClpP protease is found across eukaryotic and prokaryotic organisms. It is well-characterized in bacteria where its function is important in maintaining protein homeostasis. Along with its ATPase partners, it has been shown to play critical roles in the regulation of enzymes involved in important cellular pathways. In eukaryotes, ClpP is found within cellular organelles. Proteomic studies have begun to characterize the role of this protease in the mitochondria through its interactions. Here, we discuss the proteomic techniques used to identify its interactors and present an atlas of mitochondrial ClpP substrates. The ClpP substrate pool is extensive and consists of proteins involved in essential mitochondrial processes such as the Krebs cycle, oxidative phosphorylation, translation, fatty acid metabolism, and amino acid metabolism. Discoveries of these associations have begun to illustrate the functional significance of ClpP in human health and disease.
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Affiliation(s)
- Mark F Mabanglo
- Department of Biochemistry, University of Toronto, Toronto, Ontario, M5G 1M1, Canada
| | - Vaibhav Bhandari
- Department of Biochemistry, University of Toronto, Toronto, Ontario, M5G 1M1, Canada
| | - Walid A Houry
- Department of Biochemistry, University of Toronto, Toronto, Ontario, M5G 1M1, Canada; Department of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6, Canada.
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Sahib S, Sharma A, Muresanu DF, Zhang Z, Li C, Tian ZR, Buzoianu AD, Lafuente JV, Castellani RJ, Nozari A, Patnaik R, Menon PK, Wiklund L, Sharma HS. Nanodelivery of traditional Chinese Gingko Biloba extract EGb-761 and bilobalide BN-52021 induces superior neuroprotective effects on pathophysiology of heat stroke. PROGRESS IN BRAIN RESEARCH 2021; 265:249-315. [PMID: 34560923 DOI: 10.1016/bs.pbr.2021.06.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Military personnel often exposed to high summer heat are vulnerable to heat stroke (HS) resulting in abnormal brain function and mental anomalies. There are reasons to believe that leakage of the blood-brain barrier (BBB) due to hyperthermia and development of brain edema could result in brain pathology. Thus, exploration of suitable therapeutic strategies is needed to induce neuroprotection in HS. Extracts of Gingko Biloba (EGb-761) is traditionally used in a variety of mental disorders in Chinese traditional medicine since ages. In this chapter, effects of TiO2 nanowired EGb-761 and BN-52021 delivery to treat brain pathologies in HS is discussed based on our own investigations. We observed that TiO2 nanowired delivery of EGb-761 or TiO2 BN-52021 is able to attenuate more that 80% reduction in the brain pathology in HS as compared to conventional drug delivery. The functional outcome after HS is also significantly improved by nanowired delivery of EGb-761 and BN-52021. These observations are the first to suggest that nanowired delivery of EGb-761 and BN-52021 has superior therapeutic effects in HS not reported earlier. The clinical significance in relation to the military medicine is discussed.
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Affiliation(s)
- Seaab Sahib
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Zhiqiang Zhang
- Department of Neurosurgery, Chinese Medicine Hospital of Guangdong Province, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Yuexiu, Guangzhou, China
| | - Cong Li
- Department of Neurosurgery, Chinese Medicine Hospital of Guangdong Province, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Yuexiu, Guangzhou, China
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - José Vicente Lafuente
- LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Rudy J Castellani
- Department of Pathology, University of Maryland, Baltimore, MD, United States
| | - Ala Nozari
- Anesthesiology & Intensive Care, Massachusetts General Hospital, Boston, MA, United States
| | - Ranjana Patnaik
- Department of Biomaterials, School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - Preeti K Menon
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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De Matteis V, Cascione M, Rizzello L, Manno DE, Di Guglielmo C, Rinaldi R. Synergistic Effect Induced by Gold Nanoparticles with Polyphenols Shell during Thermal Therapy: Macrophage Inflammatory Response and Cancer Cell Death Assessment. Cancers (Basel) 2021; 13:3610. [PMID: 34298823 PMCID: PMC8303381 DOI: 10.3390/cancers13143610] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In recent decades, gold nanoparticle (Au NP)-based cancer therapy has been heavily debated. The physico-chemical properties of AuNPs can be exploited in photothermal therapy, making them a powerful tool for selectively killing cancer cells. However, the synthetic side products and capping agents often induce a strong activation of the inflammatory pathways of macrophages, thus limiting their further applications in vivo. METHODS Here, we described a green method to obtain stable polyphenol-capped AuNPs (Au NPs@polyphenols), as polyphenols are known for their anti-inflammatory and anticancer properties. These NPs were used in human macrophages to test key inflammation-related markers, such as NF-κB, TNF-α, and interleukins-6 and 8. The results were compared with similar NPs obtained by a traditional chemical route (without the polyphenol coating), proving the potential of Au NPs@polyphenols to strongly promote the shutdown of inflammation. This was useful in developing them for use as heat-synergized tools in the thermal treatment of two types of cancer cells, namely, breast cancer (MCF-7) and neuroblastoma (SH-SY5Y) cells. The cell viability, calcium release, oxidative stress, HSP-70 expression, mitochondrial, and DNA damage, as well as cytoskeleton alteration, were evaluated. RESULTS Our results clearly demonstrate that the combined strategy markedly exerts anticancer effects against the tested cancer cell, while neither of the single treatments (only heat or only NPs) induced significant changes. CONCLUSIONS Au NP@polyphenols may be powerful agents in cancer treatment.
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Affiliation(s)
- Valeria De Matteis
- Department of Mathematics and Physics “Ennio De Giorgi”, University of Salento, Via Arnesano, 73100 Lecce, Italy; (M.C.); (D.E.M.); (R.R.)
| | - Mariafrancesca Cascione
- Department of Mathematics and Physics “Ennio De Giorgi”, University of Salento, Via Arnesano, 73100 Lecce, Italy; (M.C.); (D.E.M.); (R.R.)
| | - Loris Rizzello
- Department of Pharmaceutical Sciences (DISFARM), University of Milan, Via G. Balzaretti 9, 20133 Milan, Italy;
- National Institute of Molecular Genetics (INGM), Via F. Sforza 35, 20122 Milan, Italy
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain;
| | - Daniela Erminia Manno
- Department of Mathematics and Physics “Ennio De Giorgi”, University of Salento, Via Arnesano, 73100 Lecce, Italy; (M.C.); (D.E.M.); (R.R.)
| | - Claudia Di Guglielmo
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain;
| | - Rosaria Rinaldi
- Department of Mathematics and Physics “Ennio De Giorgi”, University of Salento, Via Arnesano, 73100 Lecce, Italy; (M.C.); (D.E.M.); (R.R.)
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Natural Products of the Fungal Genus Humicola: Diversity, Biological Activity, and Industrial Importance. Curr Microbiol 2021; 78:2488-2509. [PMID: 34003333 DOI: 10.1007/s00284-021-02533-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 05/03/2021] [Indexed: 12/21/2022]
Abstract
Fungal metabolites are worthily taken into account as a pool of synthetically interesting and remarkably important new lead compounds for medical, agricultural, and chemical industries. Humicola species are known to have biotechnological and industrial potentials. Humicola genus (family Chaetomiaceae) is a prosperous fountainhead of unique and structurally diverse metabolites that have various bioactivities. Moreover, Humicola species attract substantial attention for their marked ability to produce thermostable enzymes with biotechnological and industrial importance. This review highlights the published researches on the isolated metabolites from the genus Humicola and their biological activities as well as the industrial importance of Humicola species. In the current review, more than 50 compounds are described and 84 references are cited.
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Azambuja G, Martins IK, Franco JL, Dos Santos TG. Effects of mancozeb on heat Shock protein 70 (HSP70) and its relationship with the thermal physiology of Physalaemus henselii (Peters, 1872) tadpoles (Anura: Leptodactylidae). J Therm Biol 2021; 98:102911. [PMID: 34016338 DOI: 10.1016/j.jtherbio.2021.102911] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 03/11/2021] [Accepted: 03/11/2021] [Indexed: 11/26/2022]
Abstract
Negative impacts on amphibians have been reported due to contamination by agrochemicals. However, until now, no study has tested the effect of the fungicide mancozeb (MZ) on thermal tolerance and its relationship with the expression of heat shock proteins (HSPs). MZ is the best-selling broad-spectrum fungicide in the world, which negatively affects non-target organisms. Here, we tested for the first time the effects of MZ on critical thermal maximum (CTmax) and its relationship to the expression of heat shock protein 70 (HSP70) in tadpoles of Physalameus henselii, a colder-adapted species in southernmost of the Neotropical region. A sublethal concentration of 2 mg/L was used. We found that the CTmax of the MZ-treated group was lower than that of the control group. In addition, there was an increase in HSP70 expression in tadpoles exposed to MZ and in tadpoles that underwent heat treatment. However, tadpoles subjected to MZ and heat treatment showed no induced HSP70 protein expression. Our results demonstrated that sublethal doses of the fungicide MZ negatively affected the thermal physiology and heat shock protein expression in tadpoles of P. henselii by inducing an increase in HSP70 concentration and by reducing the critical CTmax supported by tadpoles. It is important to understand the relationship between environmental contamination and physiological thermal limits in our current scenario of high rates of habitat conversion associated with unrestricted use of agrochemicals, as well as the challenging environmental changes induced by global warming.
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Affiliation(s)
- Guilherme Azambuja
- Universidade Federal de Santa Maria,Av. Roraima, Nº 1000, Santa Maria, RS, Brazil.
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Daneri-Becerra C, Valeiras B, Gallo LI, Lagadari M, Galigniana MD. Cyclophilin A is a mitochondrial factor that forms complexes with p23 - correlative evidence for an anti-apoptotic action. J Cell Sci 2021; 134:jcs.253401. [PMID: 33361281 DOI: 10.1242/jcs.253401] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 12/15/2020] [Indexed: 12/22/2022] Open
Abstract
Cyclophilin A (CyPA, also known as PPIA) is an abundant and ubiquitously expressed protein belonging to the immunophilin family, which has intrinsic peptidyl-prolyl-(cis/trans)-isomerase enzymatic activity. CyPA mediates immunosuppressive action of the cyclic undecapeptide cyclosporine A and is also involved in multiple cellular processes, such as protein folding, intracellular trafficking, signal transduction and transcriptional regulation. CyPA is abundantly expressed in cancer cells, and, owing to its chaperone nature, its expression is induced upon the onset of stress. In this study, we demonstrated that a significant pool of this immunophilin is primarily an intramitochondrial factor that migrates to the nucleus when cells are stimulated with stressors. CyPA shows anti-apoptotic action per se and the capability of forming ternary complexes with cytochrome c and the small acidic co-chaperone p23, the latter interaction being independent of the usual association of p23 with the heat-shock protein of 90 kDa, Hsp90. These CyPA•p23 complexes enhance the anti-apoptotic response of the cell, suggesting that both proteins form a functional unit, the high level of expression of which plays a significant role in cell survival.
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Affiliation(s)
- Cristina Daneri-Becerra
- Instituto de Biología y Medicina Experimental-Consejo Nacional de Investigaciones, Científicas y Técnicas (CONICET), Buenos Aires C1428ADN, Argentina
| | - Brenda Valeiras
- Instituto de Biología y Medicina Experimental-Consejo Nacional de Investigaciones, Científicas y Técnicas (CONICET), Buenos Aires C1428ADN, Argentina
| | - Luciana I Gallo
- Instituto de Fisiología, Biología Molecular y Neurociencias CONICET/Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina
| | - Mariana Lagadari
- Instituto de Biología y Medicina Experimental-Consejo Nacional de Investigaciones, Científicas y Técnicas (CONICET), Buenos Aires C1428ADN, Argentina
| | - Mario D Galigniana
- Instituto de Biología y Medicina Experimental-Consejo Nacional de Investigaciones, Científicas y Técnicas (CONICET), Buenos Aires C1428ADN, Argentina .,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina
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Chakafana G, Shonhai A. The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer. Cells 2021; 10:254. [PMID: 33525518 PMCID: PMC7911927 DOI: 10.3390/cells10020254] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/21/2021] [Accepted: 01/26/2021] [Indexed: 02/06/2023] Open
Abstract
Although cancers account for over 16% of all global deaths annually, at present, no reliable therapies exist for most types of the disease. As protein folding facilitators, heat shock proteins (Hsps) play an important role in cancer development. Not surprisingly, Hsps are among leading anticancer drug targets. Generally, Hsp70s are divided into two main subtypes: canonical Hsp70 (Escherichia coli Hsp70/DnaK homologues) and the non-canonical (Hsp110 and Grp170) members. These two main Hsp70 groups are delineated from each other by distinct structural and functional specifications. Non-canonical Hsp70s are considered as holdase chaperones, while canonical Hsp70s are refoldases. This unique characteristic feature is mirrored by the distinct structural features of these two groups of chaperones. Hsp110/Grp170 members are larger as they possess an extended acidic insertion in their substrate binding domains. While the role of canonical Hsp70s in cancer has received a fair share of attention, the roles of non-canonical Hsp70s in cancer development has received less attention in comparison. In the current review, we discuss the structure-function features of non-canonical Hsp70s members and how these features impact their role in cancer development. We further mapped out their interactome and discussed the prospects of targeting these proteins in cancer therapy.
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Affiliation(s)
| | - Addmore Shonhai
- Department of Biochemistry, University of Venda, Private Bag X5050, 0950 Thohoyandou, South Africa
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Heat Shock Protein 90α Provides an Effective and Novel Diagnosis Strategy for Nasopharyngeal Carcinoma. Adv Ther 2021; 38:413-422. [PMID: 33141414 DOI: 10.1007/s12325-020-01518-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 09/28/2020] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated tumor occurring in southeastern Asia. Due to insidious onset, it is difficult to diagnose NPC from clinical symptoms. Thus, there is an urgent need for non-invasive, high-performance biomarkers to aid the clinical diagnosis of NPC. Heat shock protein 90α (HSP90α) is an important member of the heat shock protein family that significantly increases under stress conditions such as oxidation and tumors. This is the first investigation of the role of Hsp90α in the diagnosis and progress of NPC. METHODS Plasma Hsp90α was detected by ELISA in 196 newly diagnosed NPC patients, 76 corresponding post-treatment NPC patients, 230 VCA-IgA-positive normal subjects and 106 healthy controls. RESULTS (1) The level of Hsp90α in plasma of 196 NPC patients was (212.16 ± 144.32) ng/ml, which was significantly higher than that in VCA-IgA-positive normal subjects (68.12 ± 64.94 ng/ml, P < 0.001) and healthy controls (35.87 ± 17.47 ng/ml, P < 0.001); (2) the levels of Hsp90α in patients with NPC in the early stage (I + II), stage III and stage IV were significantly different (159.69 ± 117.12 pg/ml vs. 195.24 ± 126.38 pg/ml vs. 250.85 ± 164.66 pg/ml, P = 0.018 and P = 0.029, respectively). The level of Hsp90α in plasma in patients with metastasis of NPC and those without metastasis was significantly different (P < 0.001); (3) Hsp90α is closely related to EBV DNA levels, but not to the VCA-IgA titer and EA-IgA titer; (4) the levels of Hsp90α in plasma of patients with NPC before and after treatment were significantly different (212.16 ± 144.32 pg/ml vs. 62.36 ± 34.04 pg/ml, P < 0.001); (5) the ROC curves demonstrated that the sensitivity of plasma Hsp90α in distinguishing NPC patients from healthy controls was 74.50% and the specificity was 99.10% (AUC = 0.931, 95% CI 0.903-0.958). CONCLUSION The study found that the plasma HSP90α level is closely related to the clinical stage, metastasis and therapeutic effect of NPC. HSP90α may serve as a new biomarker for diagnosis and treatment of NPC.
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Ghosh P, O'Neill BE, Li KC. Targeted Imaging Agent to HSP70 Induced In Vivo. Mol Imaging 2020; 19:1536012120942685. [PMID: 33216684 PMCID: PMC7682199 DOI: 10.1177/1536012120942685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Heat shock protein expression can be induced by heat shock making it possible to artificially modulate their levels noninvasively in vivo in a spatially and temporally controlled manner. Here, we report the use of the major heat shock protein 70 (HSP70) as an inducible target by using the small molecule deoxyspergualin (DSG) conjugated to the near-infrared fluorophore (Cy5.5). We demonstrate that heat induction in the form of localized hyperthermia of normal tissue in living mice results in sufficient HSP70 overexpression for detection with DSG-Cy5.5 conjugate. This effect is dependent on total energy delivered and reaches maximum fluorescence signal in 6 to 8 hours post heat induction and declines over a period of up to 24 hours. These results suggest that DSG-Cy5.5 agent accumulates in tissue with elevated HSP70 by heat.
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Affiliation(s)
- Pradip Ghosh
- Department of Neurology, UT Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Brian E O'Neill
- Department of Radiology, 167626The Methodist Hospital Research Institute, Houston, TX, USA
| | - King C Li
- Carle Illinois College of Medicine, 14589University of Illinois, Champaign, IL, USA
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Wang L, Xu X, Jiang Z, You Q. Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery. Acta Pharm Sin B 2020; 10:1904-1925. [PMID: 33163343 PMCID: PMC7606112 DOI: 10.1016/j.apsb.2020.01.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/10/2019] [Accepted: 01/20/2020] [Indexed: 12/14/2022] Open
Abstract
Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level, which acts as an orientation to develop drugs with new mechanisms. The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein–protein interactions (PPIs) with their client proteins. With the help of molecular chaperone machinery, the processes of protein folding, trafficking, quality control and degradation of client proteins could be arranged properly. The core members of molecular chaperones, including heat shock proteins (HSPs) family and their co-chaperones, are emerging as potential drug targets since they are involved in numerous disease conditions. Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones, co-chaperones and clients is attracting more and more attention. These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases. Here, we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.
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Affiliation(s)
- Lei Wang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaoli Xu
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Zhengyu Jiang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors. Tel./fax: +86 25 83271351.
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors. Tel./fax: +86 25 83271351.
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Roufayel R, Kadry S. Molecular Chaperone HSP70 and Key Regulators of Apoptosis - A Review. Curr Mol Med 2020; 19:315-325. [PMID: 30914024 DOI: 10.2174/1566524019666190326114720] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 03/14/2019] [Accepted: 03/19/2019] [Indexed: 02/06/2023]
Abstract
Identified as a molecular chaperone constitutively being synthesized due to enhanced elevated temperature change, this heat shock protein HSP70 has shown to be intimately involved in many protein biogenesis, facilitating the synthesis and folding of proteins and trafficking of nascent peptides during cell growth. HSP70 also plays a vital role in protein assembly, regulation and interaction with a wide variety of proteins. Stress-induced cell death is under the control of the Bcl-2 family of apoptotic regulators and display either pro-apoptotic or anti-apoptotic activities. Subjected to stress conditions such as heat shock, cells have been reported to express elevated expressions of HSP70. Moreover, this molecular chaperon has shown to act at multiple levels to suppress stressed-induced apoptotic signals of some Bcl-2 members by repairing, re-synthesizing damaged proteins, and stabilizing unfolded proteins. Therefore, HSP70 synthesis can act as an essential recovery mode for cellular survival and adaptation during lethal conditions.
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Affiliation(s)
- Rabih Roufayel
- Department of Science, College of Engineering and Technology, American University of the Middle East, Egaila, Kuwait
| | - Seifedine Kadry
- Department of Mathematics and Computer Science, Faculty of Science, Beirut Arab University, Beirut, Lebanon
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Decreased expression of FBXW7 by ERK1/2 activation in drug-resistant cancer cells confers transcriptional activation of MDR1 by suppression of ubiquitin degradation of HSF1. Cell Death Dis 2020; 11:395. [PMID: 32457290 PMCID: PMC7251134 DOI: 10.1038/s41419-020-2600-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 05/07/2020] [Accepted: 05/11/2020] [Indexed: 01/24/2023]
Abstract
The acquisition of MDR1-mediated chemoresistance poses a major obstacle to the success of conventional chemotherapeutic agents. HSF1 is also involved in chemoresistance, and several studies have demonstrated the relationship between HSF1 and MDR1 but without any consistent results. Paclitaxel- and doxorubicin-resistant cancer cells showed higher expression of MDR1 and HSF1. Depletion of HSF1 decreased mdr1 expression at mRNA level, and HSF1 directly interacted with the promoter site of mdr1, suggesting its role as a transcriptional regulator of MDR1. Phosphorylation of Ser303/307, which was involved in protein stability of HSF1 by FBXW7-mediated degradation, was found to be important for transcriptional activation of mdr1. Drug-resistant cells showed decreased expression of FBXW7, which was mediated by the activation of ERK1/2, thus indicating that over-activation of ERK1/2 in drug-resistant cells decreased FBXW7 protein stability, which finally inhibited protein degradation of pHSF1 at Ser303/307. There was a positive correlation between immunofluorescence data of pHSF1 at Ser303/307 and MDR1 in carcinogen-induced rat mammary tumors and human lung cancers. These findings identified the post-translational mechanisms of HSF1 transcription in MDR1 regulation of drug resistance development.
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The Relationship of Immunoexpression of Ki-67 and Hsp70 with Clinical and Morphological Parameters and Prognosis of Papillary Thyroid Cancer. Bull Exp Biol Med 2020; 168:688-693. [PMID: 32248456 DOI: 10.1007/s10517-020-04781-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Indexed: 12/24/2022]
Abstract
We studied the correlations of the expression of Ki-67 proliferation marker and localization of heat shock protein Hsp70 in tumor cells of papillary thyroid cancer with some clinical and morphological parameters and a 10-year survival prognosis. High variability of the proliferative activity (by Ki-67 index) of tumor cells was revealed. It was found that Hsp70 protein has different localization in tumor cells: cytoplasmic, nuclear, nucleolar, and mixed. Nuclear translocation of the Hsp70 protein correlated with the stage of the process and the prognosis of the disease, but did not correlate with sex, tumor size, capsule invasion, and lymph node metastasis. Ki-67 index of tumor cells correlated with sex, stage of the process, size of tumor formation and prognosis, but did not correlated with age, invasion into the capsule and metastasis to the lymph nodes. Depending on the variants of Hsp70 and Ki-67 co-expression, three molecular types of papillary thyroid cancer can be distinguished: favorable, intermediate, and poor prognosis.
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Albakova Z, Armeev GA, Kanevskiy LM, Kovalenko EI, Sapozhnikov AM. HSP70 Multi-Functionality in Cancer. Cells 2020; 9:cells9030587. [PMID: 32121660 PMCID: PMC7140411 DOI: 10.3390/cells9030587] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/20/2020] [Accepted: 02/28/2020] [Indexed: 12/20/2022] Open
Abstract
The 70-kDa heat shock proteins (HSP70s) are abundantly present in cancer, providing malignant cells selective advantage by suppressing multiple apoptotic pathways, regulating necrosis, bypassing cellular senescence program, interfering with tumor immunity, promoting angiogenesis and supporting metastasis. This direct involvement of HSP70 in most of the cancer hallmarks explains the phenomenon of cancer "addiction" to HSP70, tightly linking tumor survival and growth to the HSP70 expression. HSP70 operates in different states through its catalytic cycle, suggesting that it can multi-function in malignant cells in any of these states. Clinically, tumor cells intensively release HSP70 in extracellular microenvironment, resulting in diverse outcomes for patient survival. Given its clinical significance, small molecule inhibitors were developed to target different sites of the HSP70 machinery. Furthermore, several HSP70-based immunotherapy approaches were assessed in clinical trials. This review will explore different roles of HSP70 on cancer progression and emphasize the importance of understanding the flexibility of HSP70 nature for future development of anti-cancer therapies.
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Affiliation(s)
- Zarema Albakova
- Department of Biology, Lomonosov Moscow State University, 119192 Moscow, Russia; (G.A.A.); (A.M.S.)
- Department of Immunology, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.M.K.); (E.I.K.)
- Correspondence:
| | - Grigoriy A. Armeev
- Department of Biology, Lomonosov Moscow State University, 119192 Moscow, Russia; (G.A.A.); (A.M.S.)
| | - Leonid M. Kanevskiy
- Department of Immunology, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.M.K.); (E.I.K.)
| | - Elena I. Kovalenko
- Department of Immunology, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.M.K.); (E.I.K.)
| | - Alexander M. Sapozhnikov
- Department of Biology, Lomonosov Moscow State University, 119192 Moscow, Russia; (G.A.A.); (A.M.S.)
- Department of Immunology, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.M.K.); (E.I.K.)
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Milani A, Basirnejad M, Bolhassani A. Heat-shock proteins in diagnosis and treatment: an overview of different biochemical and immunological functions. Immunotherapy 2020; 11:215-239. [PMID: 30730280 DOI: 10.2217/imt-2018-0105] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Heat-shock proteins (HSPs) have been involved in different functions including chaperone activity, protein folding, apoptosis, autophagy and immunity. The HSP families have powerful effects on the stimulation of innate immune responses through Toll-like receptors and scavenger receptors. Moreover, HSP-mediated phagocytosis directly enhances the processing and presentation of internalized antigens via the endocytic pathway in adaptive immune system. These properties of HSPs have been used for development of prophylactic and therapeutic vaccines against infectious and noninfectious diseases. Several studies also demonstrated the relationship between HSPs and drug resistance as well as their use as a novel biomarker for detecting tumors in patients. The present review describes different roles of HSPs in biology and medicine especially biochemical and immunological aspects.
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Affiliation(s)
- Alireza Milani
- Department of Hepatitis & AIDS, Pasteur Institute of Iran, Tehran, Iran.,Iranian Comprehensive Hemophilia Care Center, Tehran, Iran
| | | | - Azam Bolhassani
- Department of Hepatitis & AIDS, Pasteur Institute of Iran, Tehran, Iran
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Roufayel R, Kadry S. Examination of the Role of miR-23a in the Development of Thermotolerance. Curr Mol Med 2019; 20:194-201. [PMID: 31736444 DOI: 10.2174/1566524019666191021111028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 09/30/2019] [Accepted: 10/03/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Thermotolerance is an acquired state of increased heat resistance that occurs following exposure to non-lethal proteotoxic stress. A large body of evidences implicates that molecular chaperon members belonging to the heat shock protein family could be acting as potential mediators of the thermotolerant state. OBJECTIVE Recent evidence has demonstrated heat shock proteins HSP90, HSP70 and HSP27 have inhibited heat-induced cell death by intervening at various steps in stressinduced apoptotic pathways. Previous studies have shown that HSP70 prevented heatinduced apoptosis by preventing the NOXA dependent decrease in MCL-1 levels leading to both BAX activation and cytochrome c release from mitochondria. We have also demonstrated that HSP70 expressing cells have enhanced levels of miR-23a prevent heat-induced increase in NOXA levels and suppress apoptosis. METHODS Stably transfected cell lines expressing either a control shRNA or a miR-23a targeting shRNA are quantified using both RT-PCR and semi-quantitative RT-PCR to determine the effect of different hyperthermic exposure treatment on miR-23a and Noxa mRNA expression levels. RESULTS This study shows that thermotolerant-induced pre-heat shock treatment is capable of increasing miR-23a levels. Furthermore, stable cell clones expressing a miR- 23a targeting shRNA having reduced miR-23a levels are incapable of developing a thermotolerance state, leading to apoptosis. CONCLUSION These results demonstrate the novel finding that miR-23a is an important factor in the development of the thermotolerant state.
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Affiliation(s)
- Rabih Roufayel
- College of Engineering and Technology, American University of the Middle East, Kuwait.,Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, Notario, N1G 2W1, Canada
| | - Seifedine Kadry
- Department of Mathematics and Computer Science, Faculty of Science, Beirut Arab University, Lebanon
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40
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Wong KS, Houry WA. Chemical Modulation of Human Mitochondrial ClpP: Potential Application in Cancer Therapeutics. ACS Chem Biol 2019; 14:2349-2360. [PMID: 31241890 DOI: 10.1021/acschembio.9b00347] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The human ClpP proteolytic complex (HsClpP) is a serine protease located in the mitochondrial matrix and participates in the maintenance of the mitochondrial proteome among other cellular functions. HsClpP typically forms a multimeric complex with the AAA+ protein unfoldase HsClpX. Notably, compared to that of normal, healthy cells, the expression of HsClpP in many types of solid and nonsolid cancers is found to be upregulated. While the exact role of HsClpP in tumorigenesis is not clear, certain types of cancers are highly dependent on the protease for cell proliferation and metastasis. In light of these observations, recent research has focused on the discovery and characterization of small organic molecules that can target and modulate HsClpP activity. These include compounds that inhibit HsClpP's proteolytic activity via covalent modification of its catalytic Ser residue as well as those that activate and dysregulate HsClpP by displacing HsClpX to negate its regulatory role. Importantly, several of these compounds have been shown to induce HsClpP-dependent apoptotic cell death in a variety of cancerous cells. This review provides an overview of these research efforts and highlights the various types of small molecule modulators of HsClpP activity with respect to their potential use as cancer therapeutics.
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Affiliation(s)
- Keith S. Wong
- Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1M1, Canada
| | - Walid A. Houry
- Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1M1, Canada
- Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
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41
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Lacerda R, Menezes J, Candeias MM. Alternative Mechanisms of mRNA Translation Initiation in Cellular Stress Response and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1157:117-132. [PMID: 31342440 DOI: 10.1007/978-3-030-19966-1_6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Throughout evolution, eukaryotic cells have devised different mechanisms to cope with stressful environments. When eukaryotic cells are exposed to stress stimuli, they activate adaptive pathways that allow them to restore cellular homeostasis. Most types of stress stimuli have been reported to induce a decrease in overall protein synthesis accompanied by induction of alternative mechanisms of mRNA translation initiation. Here, we present well-studied and recent examples of such stress responses and the alternative translation initiation mechanisms they induce, and discuss the consequences of such regulation for cell homeostasis and oncogenic transformation.
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Affiliation(s)
- Rafaela Lacerda
- Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, Lisboa, Portugal.,Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, University of Lisbon, Lisboa, Portugal
| | - Juliane Menezes
- Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, Lisboa, Portugal.,Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, University of Lisbon, Lisboa, Portugal
| | - Marco M Candeias
- Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, Lisboa, Portugal. .,MaRCU - Molecular and RNA Cancer Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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42
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Association of single nucleotide polymorphisms at HSPB1 rs7459185 and TGFB1 rs11466353 with radiation esophagitis in lung cancer. Radiother Oncol 2019; 135:161-169. [DOI: 10.1016/j.radonc.2019.03.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 01/10/2019] [Accepted: 03/07/2019] [Indexed: 12/25/2022]
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43
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Increase of Hspa1a and Hspa1b genes in the resting B cells of Sirt1 knockout mice. Mol Biol Rep 2019; 46:4225-4234. [DOI: 10.1007/s11033-019-04876-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 05/14/2019] [Indexed: 01/12/2023]
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44
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Frezzato F, Raggi F, Martini V, Severin F, Trimarco V, Visentin A, Scomazzon E, Accordi B, Bresolin S, Piazza F, Facco M, Basso G, Semenzato G, Trentin L. HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia. Int J Cancer 2019; 145:3089-3100. [PMID: 31044428 DOI: 10.1002/ijc.32383] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 04/16/2019] [Indexed: 02/06/2023]
Abstract
Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL). We found both HSP70 and HSF1 overexpressed in CLL patients, correlated to poor prognosis and abnormally localized in the nucleus of leukemic B cells. The two proteins were strictly correlated each other and their levels decreased consensually in those patients responding to in vivo therapeutic regimens. HSP70 and HSF1 inhibition was proved to be effective in inducing a dose-dependent in vitro apoptosis of CLL B cells. Considering that HSF1 is finely regulated by kinases belonging to pathways triggered by rat sarcoma (RAS), we benefited from a previous proteomic study performed in CLL patients aiming to assess the activation/expression of key signaling proteins. We found that patients showing high levels of HSP70 also expressed high Akt-Ser473, thus activating HSF1. Inhibition of PI3K, which activates AKT, reduced the expression of HSF1 and HSP70. By contrast, HSP70-low patients displayed high activation of MEK1/2 and ERK1/2, known to negatively regulate HSF1. These data demonstrate that the HSP70 expression is regulated by the modulation of HSF1 activity through the activation of RAS-regulated pathways and suggest the HSP70/HSF1 interplay as an interesting target for antileukemic therapies. Finally, inhibition of PI3K, that activates AKT, reduced the expression of HSF1 and HSP70.
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Affiliation(s)
- Federica Frezzato
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.,Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Flavia Raggi
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.,Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Veronica Martini
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.,Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Filippo Severin
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.,Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Valentina Trimarco
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy
| | - Andrea Visentin
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy
| | - Edoardo Scomazzon
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy
| | - Benedetta Accordi
- Department of Woman's and Child's Health, University of Padua, Padua, Italy
| | - Silvia Bresolin
- Department of Woman's and Child's Health, University of Padua, Padua, Italy
| | - Francesco Piazza
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.,Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Monica Facco
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.,Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Giuseppe Basso
- Department of Woman's and Child's Health, University of Padua, Padua, Italy
| | - Gianpietro Semenzato
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.,Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Livio Trentin
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.,Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
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45
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Cho W, Jin X, Pang J, Wang Y, Mivechi NF, Moskophidis D. The Molecular Chaperone Heat Shock Protein 70 Controls Liver Cancer Initiation and Progression by Regulating Adaptive DNA Damage and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling Pathways. Mol Cell Biol 2019; 39:e00391-18. [PMID: 30745413 PMCID: PMC6469921 DOI: 10.1128/mcb.00391-18] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 08/21/2018] [Accepted: 02/04/2019] [Indexed: 02/06/2023] Open
Abstract
Delineating the mechanisms that drive hepatic injury and hepatocellular carcinoma (HCC) progression is critical for development of novel treatments for recurrent and advanced HCC but also for the development of diagnostic and preventive strategies. Heat shock protein 70 (HSP70) acts in concert with several cochaperones and nucleotide exchange factors and plays an essential role in protein quality control that increases survival by protecting cells against environmental stressors. Specifically, the HSP70-mediated response has been implicated in the pathogenesis of cancer, but the specific mechanisms by which HSP70 may support malignant cell transformation remains to be fully elucidated. Here, we show that genetic ablation of HSP70 markedly impairs HCC initiation and progression by distinct but overlapping pathways. This includes the potentiation of the carcinogen-induced DNA damage response, at the tumor initiation stage, to increase the p53-dependent surveillance response leading to the cell cycle exit or death of genomically damaged differentiated pericentral hepatocytes, and this may also prevent their conversion into more proliferating HCC progenitor cells. Subsequently, activation of a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) negative feedback pathway diminishes oncogenic signals, thereby attenuating premalignant cell transformation and tumor progression. Modulation of HSP70 function may be a strategy for interfering with oncogenic signals driving liver cell transformation and tumor progression, thus providing an opportunity for human cancer control.
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Affiliation(s)
- Wonkyoung Cho
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Xiongjie Jin
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Junfeng Pang
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Yan Wang
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Nahid F Mivechi
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Radiology and Imaging, Augusta University, Augusta, Georgia, USA
| | - Demetrius Moskophidis
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Medicine, Augusta University, Augusta, Georgia, USA
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46
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Enguix-Riego MDV, Cacicedo J, Delgado León BD, Nieto-Guerrero Gómez JM, Herrero Rivera D, Perez M, Praena-Fernández JM, Sanchez Carmona G, Rivin Del Campo E, Ortiz Gordillo MJ, Lopez Guerra JL. The single nucleotide variant rs2868371 associates with the risk of mortality in non-small cell lung cancer patients: A multicenter prospective validation. Radiother Oncol 2019; 136:29-36. [PMID: 31015126 DOI: 10.1016/j.radonc.2019.03.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/23/2019] [Accepted: 03/26/2019] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND PURPOSE Definitive radiation therapy (RT) with or without chemotherapy has become the standard treatment for non-metastatic unresectable non-small cell lung cancer (NSCLC). However, treatment outcomes can differ substantially and patients' genetic background could play a crucial role. Potential associations between single-nucleotide polymorphisms (SNP) in Heat shock protein beta-1 (HSPB1) and survival have been reported in prior single-institution retrospective reports. MATERIALS AND METHODS The current assay aims to validate such connection in a prospective multicenter study in a European cohort including 181 NSCLC patients. Median follow-up time for all patients was 13 months (range, 3-57 months). RESULTS The results obtained show an association between the rs2868371 GG genotype and better overall survival (HR: 0.35; 95%CI: 0.13-0.96; p = 0.042) in multivariate analysis. Two-year overall survival rate was 72% for patients carrying the rs2868371 GG genotype versus 36% for those patients harboring the rs2868371 CC/CG genotypes (p = 0.013). Additionally, the rs2868371 GG genotype was found to be associated with better disease-free survival in the multivariate analysis (HR: 0.36; 95%CI: 0.13-0.99; p = 0.048). In silico analysis of the potential functional SNP suggested significant difference in the affinity of the Glucocorticoid Receptor binding site between alternative allelic variants, confirmed by chromatin immunoprecipitation analysis displaying stronger affinity for the risk allele (C). Furthermore, our findings indicate that the rs2868371 influences (mRNA) HSPB1 expression, offering insight into the regulation of HSPB1 transcription. CONCLUSION The functional HSPB1 rs2868371 promoter variant may affect lung cancer survival by regulation of HSPB1 expression levels through glucocorticoid receptor interaction.
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Affiliation(s)
- María Del Valle Enguix-Riego
- Department of Radiation Oncology, University Hospital Virgen del Rocío, Seville, Spain; Instituto de Biomedicina de Sevilla (IBIS/HUVR/CSIC/Universidad de Sevilla), Spain
| | - Jon Cacicedo
- Departament of Radiation Oncology, Cruces University Hospital, Barakaldo, Spain
| | | | | | - Daniel Herrero Rivera
- Department of Medical Oncology, University Hospital Virgen del Rocío, Seville, Spain
| | - Marco Perez
- Instituto de Biomedicina de Sevilla (IBIS/HUVR/CSIC/Universidad de Sevilla), Spain
| | | | | | | | - María José Ortiz Gordillo
- Department of Radiation Oncology, University Hospital Virgen del Rocío, Seville, Spain; Instituto de Biomedicina de Sevilla (IBIS/HUVR/CSIC/Universidad de Sevilla), Spain
| | - Jose Luis Lopez Guerra
- Department of Radiation Oncology, University Hospital Virgen del Rocío, Seville, Spain; Instituto de Biomedicina de Sevilla (IBIS/HUVR/CSIC/Universidad de Sevilla), Spain.
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Kasioumi P, Vrazeli P, Vezyraki P, Zerikiotis S, Katsouras C, Damalas A, Angelidis C. Hsp70 (HSP70A1A) downregulation enhances the metastatic ability of cancer cells. Int J Oncol 2018; 54:821-832. [PMID: 30569142 PMCID: PMC6365026 DOI: 10.3892/ijo.2018.4666] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 11/16/2018] [Indexed: 02/07/2023] Open
Abstract
Heat shock protein 70 (Hsp70; also known as HSP70A1A) is one of the most induced proteins in cancer cells; however, its role in cancer has not yet been fully elucidated. In the present study, we proposed a hypothetical model in which the silencing of Hsp70 enhanced the metastatic properties of the HeLa, A549 and MCF7 cancer cell lines. We consider that the inability of cells to form cadherin-catenin complexes in the absence of Hsp70 stimulates their detachment from neighboring cells, which is the first step of anoikis and metastasis. Under these conditions, an epithelial-to-mesenchymal transition (EMT) pathway is activated that causes cancer cells to acquire a mesenchymal phenotype, which is known to possess a higher ability for migration. Therefore, we herein provide evidence of the dual role of Hsp70 which, according to international literature, first establishes a cancerous environment and then, as suggested by our team, regulates the steps of the metastatic process, including EMT and migration. Finally, the trigger for the anti-metastatic properties that are acquired by cancer cells in the absence of Hsp70 appears to be the destruction of the Hsp70-dependent heterocomplexes of E-cadherin/catenins, which function like an anchor between neighboring cells.
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Affiliation(s)
- Panagiota Kasioumi
- Department of General Biology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Paraskevi Vrazeli
- Department of General Biology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Patra Vezyraki
- Department of Physiology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Stelios Zerikiotis
- Department of Physiology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Christos Katsouras
- Department of Cardiology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Alexander Damalas
- Biotechnology and Nanomedicine Laboratory, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Charalampos Angelidis
- Department of General Biology, Michaelideion Cardiac Centre, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
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48
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Morán Luengo T, Mayer MP, Rüdiger SGD. The Hsp70-Hsp90 Chaperone Cascade in Protein Folding. Trends Cell Biol 2018; 29:164-177. [PMID: 30502916 DOI: 10.1016/j.tcb.2018.10.004] [Citation(s) in RCA: 168] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 10/19/2018] [Accepted: 10/24/2018] [Indexed: 12/12/2022]
Abstract
Conserved families of molecular chaperones assist protein folding in the cell. Here we review the conceptual advances on three major folding routes: (i) spontaneous, chaperone-independent folding; (ii) folding assisted by repetitive Hsp70 cycles; and (iii) folding by the Hsp70-Hsp90 cascades. These chaperones prepare their protein clients for folding on their own, without altering their folding path. A particularly interesting role is reserved for Hsp90. The function of Hsp90 in folding is its ancient function downstream of Hsp70, free of cochaperone regulation and present in all kingdoms of life. Eukaryotic signalling networks, however, embrace Hsp90 by a plethora of cochaperones, transforming the profolding machinery to a folding-on-demand factor. We discuss implications for biology and molecular medicine.
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Affiliation(s)
- Tania Morán Luengo
- Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Science for Life, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
| | - Matthias P Mayer
- Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH-Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
| | - Stefan G D Rüdiger
- Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Science for Life, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
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Nandi SK, Chakraborty A, Panda AK, Kar RK, Bhunia A, Biswas A. Evidences for zinc (II) and copper (II) ion interactions with Mycobacterium leprae HSP18: Effect on its structure and chaperone function. J Inorg Biochem 2018; 188:62-75. [DOI: 10.1016/j.jinorgbio.2018.08.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/01/2018] [Accepted: 08/09/2018] [Indexed: 10/28/2022]
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50
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Sannino S, Guerriero CJ, Sabnis AJ, Stolz DB, Wallace CT, Wipf P, Watkins SC, Bivona TG, Brodsky JL. Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells. J Cell Sci 2018; 131:jcs217760. [PMID: 30131440 PMCID: PMC6140321 DOI: 10.1242/jcs.217760] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 08/02/2018] [Indexed: 12/13/2022] Open
Abstract
Cancer cells thrive when challenged with proteotoxic stress by inducing components of the protein folding, proteasome, autophagy and unfolded protein response (UPR) pathways. Consequently, specific molecular chaperones have been validated as targets for anti-cancer therapies. For example, inhibition of Hsp70 family proteins (hereafter Hsp70) in rhabdomyosarcoma triggers UPR induction and apoptosis. To define how these cancer cells respond to compromised proteostasis, we compared rhabdomyosarcoma cells that were sensitive (RMS13) or resistant (RMS13-R) to the Hsp70 inhibitor MAL3-101. We discovered that endoplasmic reticulum-associated degradation (ERAD) and autophagy were activated in RMS13-R cells, suggesting that resistant cells overcome Hsp70 ablation by increasing misfolded protein degradation. Indeed, RMS13-R cells degraded ERAD substrates more rapidly than RMS cells and induced the autophagy pathway. Surprisingly, inhibition of the proteasome or ERAD had no effect on RMS13-R cell survival, but silencing of select autophagy components or treatment with autophagy inhibitors restored MAL3-101 sensitivity and led to apoptosis. These data indicate a route through which cancer cells overcome a chaperone-based therapy, define how cells can adapt to Hsp70 inhibition, and demonstrate the value of combined chaperone and autophagy-based therapies.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Sara Sannino
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | | | - Amit J Sabnis
- Department of Pediatrics, University of California, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA
| | - Donna Beer Stolz
- Department of Medicine, University of California, San Francisco, CA 94143, USA
| | - Callen T Wallace
- Department of Medicine, University of California, San Francisco, CA 94143, USA
| | - Peter Wipf
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Simon C Watkins
- Department of Medicine, University of California, San Francisco, CA 94143, USA
| | - Trever G Bivona
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Jeffrey L Brodsky
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
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