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Shi R, Yu R, Lian F, Zheng Y, Feng S, Li C, Zheng X. Targeting HSP47 for cancer treatment. Anticancer Drugs 2024; 35:623-637. [PMID: 38718070 DOI: 10.1097/cad.0000000000001612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2024]
Abstract
Heat shock protein 47 (HSP47) serves as an endoplasmic reticulum residing collagen-specific chaperone and plays an important role in collagen biosynthesis and structural assembly. HSP47 is encoded by the SERPINH1 gene, which is located on chromosome 11q13.5, one of the most frequently amplified regions in human cancers. The expression of HSP47 is regulated by multiple cellular factors, including cytokines, transcription factors, microRNAs, and circular RNAs. HSP47 is frequently upregulated in a variety of cancers and plays an important role in tumor progression. HSP47 promotes tumor stemness, angiogenesis, growth, epithelial-mesenchymal transition, and metastatic capacity. HSP47 also regulates the efficacy of tumor therapies, such as chemotherapy, radiotherapy, and immunotherapy. Inhibition of HSP47 expression has antitumor effects, suggesting that targeting HSP47 is a feasible strategy for cancer treatment. In this review, we highlight the function and expression of regulatory mechanisms of HSP47 in cancer progression and point out the potential development of therapeutic strategies in targeting HSP47 in the future.
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Affiliation(s)
- Run Shi
- School of Medicine, Pingdingshan University, Pingdingshan, China
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Nakamura ET, Park A, Pereira MA, Kikawa D, Tustumi F. Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer: A systematic review and meta-analysis. World J Gastrointest Oncol 2024; 16:1578-1595. [PMID: 38660660 PMCID: PMC11037039 DOI: 10.4251/wjgo.v16.i4.1578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/24/2023] [Accepted: 01/23/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Heat shock proteins (HSPs) are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overexpressed in many cancers. The prognostic significance of HSPs and their regulatory factors, such as heat shock factor 1 (HSF1) and CHIP, are poorly understood. AIM To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer. METHODS A systematic review was conducted in accordance with PRISMA recommendations (PROSPERO: CRD42022370653), on Embase, PubMed, Cochrane, and LILACS. Cohort, case-control, and cross-sectional studies of patients with esophagus or esophagogastric cancer were included. HSP-positive patients were compared with HSP-negative, and the endpoints analyzed were lymph node metastasis, tumor depth, distant metastasis, and overall survival (OS). HSPs were stratified according to the HSP family, and the summary risk difference (RD) was calculated using a random-effect model. RESULTS The final selection comprised 27 studies, including esophageal squamous cell carcinoma (21), esophagogastric adenocarcinoma (5), and mixed neoplasms (1). The pooled sample size was 3465 patients. HSP40 and 60 were associated with a higher 3-year OS [HSP40: RD = 0.22; 95% confidence interval (CI): 0.09-0.35; HSP60: RD = 0.33; 95%CI: 0.17-0.50], while HSF1 was associated with a poor 3-year OS (RD = -0.22; 95%CI: -0.32 to -0.12). The other HSP families were not associated with long-term survival. HSF1 was associated with a higher probability of lymph node metastasis (RD = -0.16; 95%CI: -0.29 to -0.04). HSP40 was associated with a lower probability of lymph node dissemination (RD = 0.18; 95%CI: 0.03-0.33). The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis. CONCLUSION The expression levels of certain families of HSP, such as HSP40 and 60 and HSF1, are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.
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Affiliation(s)
- Eric Toshiyuki Nakamura
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Amanda Park
- Department of Evidence-Based Medicine, Centro Universitário Lusíada, Centre for Evidence-Based Medicine, Centro Universitário Lusíada (UNILUS), Santos, Brazil
| | - Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
| | - Daniel Kikawa
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Francisco Tustumi
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo 05652900, Brazil
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Sossa-Rojas H, Franco-Maz PG, Zapata-Acevedo C, Gutierrez-Castañeda LD, Guerrero C. Preclinical evaluation of oncolytic potential human rotavirus Wt 1-5 in gastric adenocarcinoma. PLoS One 2023; 18:e0285543. [PMID: 37186587 PMCID: PMC10184912 DOI: 10.1371/journal.pone.0285543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 04/25/2023] [Indexed: 05/17/2023] Open
Abstract
Despite advances in biomedical research, gastric cancer remains the leading cause of morbidity and mortality worldwide due to the limited efficacy of conventional therapies. In recent decades, oncolytic viruses have emerged as a biological therapeutic alternative to cancer due to their selectivity, effectiveness, and low toxicity. However, clinical trials have shown that developing a virus with selectivity for multiple tumor receptors and the ability to penetrate and diffuse through the tumor microenvironment to reactivate the immune system remains challenging. This study aimed to examine the oncolytic potential of tumor cell-adapted rotavirus Wt1-5 in gastric adenocarcinoma samples. This study focused on determining the propagation capacity of the RV Wt1-5 through the tumor and the importance of the expression of cell surface co-receptors, including integrin β3, protein disulfide isomerase (PDI), and heat shock proteins (Hsp-90, -70, -60, -40, and Hsc 70), during infection of tumor cells. These proteins were found to be differentially expressed in tumor cells compared to adjacent non-tumor cells. Preincubation of gastric tumor cells with antibodies against these proteins decreased rotavirus infections, validating their importance in the binding and entry of RV Wt1-5 into tumor cells, as previously reported. Upon RV infection, apoptosis was one of the types of death that was observed. This was evidenced by evaluating the expression of CASP-3, -9, PARP, cytochrome C, Bax, Bid, p53, and Bcl-2, as well as observing morphological changes such as chromatin margination, nuclear condensation, and fragmentation. Finally, at 60 h.p.i, histological analysis revealed that oncolysis compromised the entire thickness of the tumor. Therefore, the results suggest that RV Wt1-5 could be a novel therapeutic agent co-adjuvant agent for conventional and targeted therapies in managing GC. Ex vivo infection of the tumor tissue model showed characteristics of an immune response that could be explored in future studies.
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Affiliation(s)
- Henry Sossa-Rojas
- Departamento de Ciencias Básicas y Medicina Oral, Facultad de Odontología, Universidad Nacional de Colombia, Sede Bogotá, Bogotá, D.C., Colombia
| | - Pedro Gabriel Franco-Maz
- Departamento de Morfología, Facultad de Medicina, Universidad Nacional de Colombia, Sede Bogotá, Bogotá, D.C., Colombia
- Servicio de Patología, Hospital Universitario La Samaritana, Bogotá, D.C., Colombia
| | - Carlos Zapata-Acevedo
- Departamento de Cirugía, Facultad de Medicina, Universidad Nacional de Colombia, Sede Bogotá, Bogotá, D.C., Colombia
- Servicio de Cirugía General, Hospital Universitario La Samaritana, Bogoté, D.C., Colombia
| | - Luz Dary Gutierrez-Castañeda
- Research Institute, Grupos Ciencias Básicas en Salud - CBS-FUCS, Fundación Universitaria de Ciencias de la Salud, Hospital Infantil Universitario de San Josá, Bogotá, D.C., Colombia
| | - Carlos Guerrero
- Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad Nacional de Colombia, Sede Bogotá, Bogotá, D.C., Colombia
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Johnson OT, Gestwicki JE. Multivalent protein-protein interactions are pivotal regulators of eukaryotic Hsp70 complexes. Cell Stress Chaperones 2022; 27:397-415. [PMID: 35670950 PMCID: PMC9346034 DOI: 10.1007/s12192-022-01281-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 05/18/2022] [Accepted: 05/24/2022] [Indexed: 11/26/2022] Open
Abstract
Heat shock protein 70 (Hsp70) is a molecular chaperone and central regulator of protein homeostasis (proteostasis). Paramount to this role is Hsp70's binding to client proteins and co-chaperones to produce distinct complexes, such that understanding the protein-protein interactions (PPIs) of Hsp70 is foundational to describing its function and dysfunction in disease. Mounting evidence suggests that these PPIs include both "canonical" interactions, which are universally conserved, and "non-canonical" (or "secondary") contacts that seem to have emerged in eukaryotes. These two categories of interactions involve discrete binding surfaces, such that some clients and co-chaperones engage Hsp70 with at least two points of contact. While the contributions of canonical interactions to chaperone function are becoming increasingly clear, it can be challenging to deconvolute the roles of secondary interactions. Here, we review what is known about non-canonical contacts and highlight examples where their contributions have been parsed, giving rise to a model in which Hsp70's secondary contacts are not simply sites of additional avidity but are necessary and sufficient to impart unique functions. From this perspective, we propose that further exploration of non-canonical contacts will generate important insights into the evolution of Hsp70 systems and inspire new approaches for developing small molecules that tune Hsp70-mediated proteostasis.
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Affiliation(s)
- Oleta T Johnson
- Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, 94158, USA
| | - Jason E Gestwicki
- Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, 94158, USA.
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Yüksel C, Gündoğdu SB, Bakırarar B, Çiftçi AY, Tez M, Yıldız BD. Relationship between HSP90 protein expression
and overall survival and clinicopathological outcomes
in gastric cancer patients. POLISH JOURNAL OF SURGERY 2022; 94:51-58. [DOI: 10.5604/01.3001.0015.7551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2025]
Abstract
<br><b>Aim:</b> Gastric cancer is a highly prevalent public health problem with high morbidity and mortality. İts primary treatment is surgery. Recently, studies involving biological parameters and genetics in gastric cancer have been emerging but with many blind spots. Our study aims to investigate the clinicopathological and prognostic significance of heat shock proteins (HSP90) expression in patients with resectable gastric cancer.</br>
<br><b>Methods:</b> Single-center retrospective clinical study conducted at the General Surgery Department of the local training and research hospital. Our study involves 54 patients who had curative surgery for gastric cancer between 2011 and 2014.</br>
<br><b>Results:</b> Pathological specimens fixed in formalin and paraffin were re-evaluated with HSP90 staining and expression of HSP90 was evaluated. It was found that only 39 (72.2%) patients showed HSP90 expression. Seventeen (31.5%) of those showed mild, 13 (24.1%) had moderate, and 9 (10.5%) severe expression. HSP90 expression did not have a significant effect on survival in patients who underwent curative resection for gastric cancer, although statistically close. The effect of expression and intensity on overall survival was not statistically significant either.</br>
<br><b>Conclusions:</b> There are various reports in literature on HSP90 expression in gastric cancer – some find it to be a prognostic factor, some not. There is a number of limitations of our study as we did not include metastatic tumors, the number of patients was low, the study involved only our patients and a single pathologist. This is the first study carried out in our population on this subject. Further studies could be done to evaluate this particular relationship in an effort to possibly identify novel treatments in gastric cancer.</br>
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Affiliation(s)
- Cemil Yüksel
- Clinic of Surgical Oncology, Mersin City Training and Research Hospital, Mersin, Turkey
| | - Salih Burak Gündoğdu
- Clinic of Gastrointestinal Surgery, Health Science University Ankara City Hospital, Ankara, Turkey
| | - Batuhan Bakırarar
- Ankara University, School of Medicine, Department Biostatistics, Ankara, Turkey
| | - Ayşe Yılmaz Çiftçi
- Clinic of Pathology, Health Science University Ankara City Hospital, Ankara, Turkey
| | - Mesut Tez
- Clinic of General Surgery, Health Science University Ankara City Hospital, Ankara, Turkey
| | - Barış Doğu Yıldız
- Clinic of General Surgery, Health Science University Ankara City Hospital, Ankara, Turkey
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miR-1205/DNAJB1 reverses docetaxel chemoresistance in human triple negative breast carcinoma cells via regulation of mutp53/TAp63 signaling. Acta Biochim Biophys Sin (Shanghai) 2021; 54:37-46. [PMID: 35130632 PMCID: PMC9909320 DOI: 10.3724/abbs.2021006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Chemoresistance is the major cause of therapeutic failure in human triple negative breast carcinoma (TNBC). Docetaxel (DOC), a first-line therapeutic drug in TNBC treatment, is limited for long-term use due to the development of chemoresistance. Thus, overcoming chemoresistance of DOC remains an important challenge to improve patient's outcome of TNBC. In this study, we aimed to investigate the molecular mechanism behind DOC chemoresistance and the possible therapeutic effects of miRNAs. Utilizing qRT-PCR analysis, we discovered that miR-1205 is gradually downregulated in human triple negative breast carcinoma MDA-MB-231 and docetaxel-resistant MDA-MB-231 (MDA-MB-231/DOC) cells compared with Hs 578Bst normal human breast fibroblasts. Cell viability, cell cycle and apoptosis assays in MDA-MB-231/DOC cells indicated that miR-1205 overexpression enhances docetaxel sensitivity by reducing cell viability as well as inducing G2/M cell cycle arrest and cell apoptosis. Western blot analysis, dual-luciferase reporter assay, co-immunoprecipitation assay and chromatin immunoprecipitation assay revealed that miR-1205 overexpression disrupts the stable complex formation of DNAJB1, mutp53 and TAp63 by directly reducing DNAJB1 expression, which abates the sequestrating effect of mutp53 on TAp63, thereby leading to the enhanced DOC sensitivity in MDA-MB-231/DOC cells. Our findings demonstrate the role of the miR-1205/DNAJB1 axis in the docetaxel resistance of TNBC, which may offer a promising therapeutic approach to resolve docetaxel resistance in TNBC.
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Wang X, Xie L, Zhu L. Clinicopathological significance of HSP70 expression in gastric cancer: a systematic review and meta-analysis. BMC Gastroenterol 2021; 21:437. [PMID: 34809574 PMCID: PMC8609754 DOI: 10.1186/s12876-021-01990-4] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 10/22/2021] [Indexed: 11/13/2022] Open
Abstract
Background Heat shock protein 70 (HSP70) has been associated with the clinicopathological characteristics and prognosis of many cancers types, implying that it is a potential cancer biomarker. However, no consensus has been reached regarding its clinicopathological and prognostic significance in patients with gastric cancer. To address this gap, we performed a systematic review and meta-analysis. Methods We searched PubMed, Embase, and the Cochrane Library for full-text literature according to the eligibility criteria. We used the odds ratio and hazard ratio as the suitable parameters to evaluate the clinicopathological and prognostic significance of HSP70. The statistical analysis was performed using STATA 15.0. Results After inclusion and exclusion of studies based on the eligibility criteria, data of 1,307 patients with gastric cancer from 9 studies were finally included. The pooled outcomes implied that HSP70 expression was significantly correlated with higher differentiation degrees, intestinal gastric cancer, and lymphovascular invasion but not with age, gender, depth of invasion, Helicobacter pylori infection, lymph node invasion, TNM stages, and metastasis. The pooled HR showed no significant correlation between HSP70 expression and overall survival of gastric cancer patients. Conclusions Our meta-analysis showed that HSP70 plays a complicated role in the development of gastric cancer. It may be directly engaged in tumour differentiation and distant invasion but cannot be considered a biomarker for predicting the prognosis of gastric cancer.
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Affiliation(s)
- Xiaolu Wang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Li Xie
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Lijing Zhu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.
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Wang SF, Huang KH, Tseng WC, Lo JF, Li AFY, Fang WL, Chen CF, Yeh TS, Chang YL, Chou YC, Hung HH, Lee HC. DNAJA3/Tid1 Is Required for Mitochondrial DNA Maintenance and Regulates Migration and Invasion of Human Gastric Cancer Cells. Cancers (Basel) 2020; 12:cancers12113463. [PMID: 33233689 PMCID: PMC7699785 DOI: 10.3390/cancers12113463] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/13/2020] [Accepted: 11/18/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gastric cancer is a common health issue. Deregulated cellular energetics is regarded as a cancer hallmark and mitochondrial dysfunction might contribute to cancer progression. Tid1, a mitochondrial co-chaperone, may play a role as a tumor suppressor in various cancers, but the role of Tid1 in gastric cancers remains under investigated. METHODS The clinical TCGA online database and immunohistochemical staining for Tid1 expression in tumor samples of gastric cancer patients were analyzed. Tid1 knockdown by siRNA was applied to investigate the role of Tid1 in gastric cancer cells. RESULTS Low Tid1 protein-expressing gastric cancer patients had a poorer prognosis and higher lymph node invasion than high Tid1-expressing patients. Knockdown of Tid1 did not increase cell proliferation, colony/tumor sphere formation, or chemotherapy resistance in gastric cancer cells. However, Tid1 knockdown increased cell migration and invasion. Moreover, Tid1 knockdown reduced the mtDNA copy number of gastric cancer cells. In addition, the Tid1-galectin-7-MMP-9 axis might be associated with Tid1 knockdown-induced cell migration and invasion of gastric cancer cells. CONCLUSIONS Tid1 is required for mtDNA maintenance and regulates migration and invasion of gastric cancer cells. Tid1 deletion may be a poor prognostic factor in gastric cancers and could be further investigated for development of gastric cancer treatments.
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Affiliation(s)
- Sheng-Fan Wang
- Department of Pharmacy, Taipei Veterans General Hospital, Taipei 112, Taiwan; (S.-F.W.); (Y.-L.C.); (Y.-C.C.)
- School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (W.-C.T.); (J.-F.L.)
| | - Kuo-Hung Huang
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (K.-H.H.); (A.F.-Y.L.); (W.-L.F.)
- Department of Surgery, Division of General Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Wei-Chuan Tseng
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (W.-C.T.); (J.-F.L.)
| | - Jeng-Fan Lo
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (W.-C.T.); (J.-F.L.)
- Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei 112, Taiwan
- Institute of Oral Biology, National Yang-Ming University, Taipei 112, Taiwan
- Cancer Progression Research Center, National Yang-Ming University, Taipei 112, Taiwan;
| | - Anna Fen-Yau Li
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (K.-H.H.); (A.F.-Y.L.); (W.-L.F.)
- Department of Pathology, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Wen-Liang Fang
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (K.-H.H.); (A.F.-Y.L.); (W.-L.F.)
- Department of Surgery, Division of General Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Chian-Feng Chen
- Cancer Progression Research Center, National Yang-Ming University, Taipei 112, Taiwan;
| | - Tien-Shun Yeh
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan;
| | - Yuh-Lih Chang
- Department of Pharmacy, Taipei Veterans General Hospital, Taipei 112, Taiwan; (S.-F.W.); (Y.-L.C.); (Y.-C.C.)
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (W.-C.T.); (J.-F.L.)
- Faculty of Pharmacy, National Yang-Ming University, Taipei 112, Taiwan
| | - Yueh-Ching Chou
- Department of Pharmacy, Taipei Veterans General Hospital, Taipei 112, Taiwan; (S.-F.W.); (Y.-L.C.); (Y.-C.C.)
- School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (W.-C.T.); (J.-F.L.)
- Faculty of Pharmacy, National Yang-Ming University, Taipei 112, Taiwan
| | - Hung-Hsu Hung
- School of Medicine, Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan
- Department of Medicine, Division of Gastroenterology, Cheng Hsin General Hospital, Taipei 112, Taiwan
- Correspondence: (H.-H.H.); (H.-C.L.); Tel.: +886-2-2826-7327 (H.-C.L.)
| | - Hsin-Chen Lee
- Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; (W.-C.T.); (J.-F.L.)
- Correspondence: (H.-H.H.); (H.-C.L.); Tel.: +886-2-2826-7327 (H.-C.L.)
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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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11
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Hoter A, Naim HY. Heat Shock Proteins and Ovarian Cancer: Important Roles and Therapeutic Opportunities. Cancers (Basel) 2019; 11:E1389. [PMID: 31540420 PMCID: PMC6769485 DOI: 10.3390/cancers11091389] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/11/2019] [Accepted: 09/16/2019] [Indexed: 12/17/2022] Open
Abstract
Ovarian cancer is a serious cause of death in gynecological oncology. Delayed diagnosis and poor survival rates associated with late stages of the disease are major obstacles against treatment efforts. Heat shock proteins (HSPs) are stress responsive molecules known to be crucial in many cancer types including ovarian cancer. Clusterin (CLU), a unique chaperone protein with analogous oncogenic criteria to HSPs, has also been proven to confer resistance to anti-cancer drugs. Indeed, these chaperone molecules have been implicated in diagnosis, prognosis, metastasis and aggressiveness of various cancers. However, relative to other cancers, there is limited body of knowledge about the molecular roles of these chaperones in ovarian cancer. In the current review, we shed light on the diverse roles of HSPs as well as related chaperone proteins like CLU in the pathogenesis of ovarian cancer and elucidate their potential as effective drug targets.
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Affiliation(s)
- Abdullah Hoter
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt.
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
| | - Hassan Y Naim
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
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Sun G, Cao Y, Dai X, Li M, Guo J. Hsc70 Interacts with β4GalT5 to Regulate the Growth of Gliomas. Neuromolecular Med 2019; 21:33-41. [PMID: 30607818 DOI: 10.1007/s12017-018-08520-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 12/15/2018] [Indexed: 12/22/2022]
Abstract
Heat shock cognate protein 70 (Hsc70) is a key mediator for the maintenance of intracellular proteins and regulates cellular activities. And it is elevated in various tumor tissues including glioma, which is closely related to the malignancy and poor prognosis of the tumors. However, the effects of Hsc70 on gliomas and its regulatory mechanism have not yet been elucidated. In the present study, we found that Hsc70 was overexpressed in glioma tissues and cultured glioma cells. Furthermore, Hsc70 expression exhibited positive correlation with the grades of gliomas. Knockdown of Hsc70 could effectively inhibit cell proliferation and increase cell apoptosis. Furthermore, we identified that β4GalT5 was a critical target for Hsc70-mediated anti-glioma effects. Blocking β4GalT5 activity could effectively reverse the anti-tumor effect of Hsc70. Taken together, these data indicate that Hsc70 regulates β4GalT5 levels, and possibly plays a role in cell proliferation and apoptosis of glioma.
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Affiliation(s)
- Guan Sun
- Department of Neurosurgery, Yancheng City No. 1 People's Hospital, The Fourth Affiliated Hospital of Nantong University, Yancheng, 224001, People's Republic of China
| | - Ying Cao
- Department of Ear-Nose-Throat, The Second People's Hospital of Huai'An, Huai'An Affiliated Hospital of Xuzhou Medical University, Huai'an, People's Republic of China
| | - Xueliang Dai
- Department of Neurosurgery, Zoucheng Peoples' Hospital, Zoucheng, People's Republic of China
| | - Min Li
- Department of Neurosurgery, Jiangning Hospital Affiliated with Nanjing Medical University, Nanjing, 211100, People's Republic of China.
| | - Jun Guo
- Department of Neurosurgery, Yancheng City No. 1 People's Hospital, The Fourth Affiliated Hospital of Nantong University, Yancheng, 224001, People's Republic of China.
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Balzan S, Lubrano V. LOX-1 receptor: A potential link in atherosclerosis and cancer. Life Sci 2018; 198:79-86. [PMID: 29462603 DOI: 10.1016/j.lfs.2018.02.024] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 02/07/2018] [Accepted: 02/16/2018] [Indexed: 12/19/2022]
Abstract
Altered production of reactive oxygen species (ROS), causing lipid peroxidation and DNA damage, contributes to the progression of atherosclerosis and cancer. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a lectin-like receptor for oxidized low-density lipoproteins (ox-LDL) primarily expressed in endothelial cells and vasculature-rich organs. LOX-1 receptors is a marker for atherosclerosis, and once activated by ox-LDL or other ligands, stimulates the expression of adhesion molecules, pro-inflammatory signaling pathways and proangiogenic proteins, including NF-kB and VEGF, in vascular endothelial cells and macrophages. Several different types of cancer reported LOX-1 gene upregulation, and numerous interplays exist concerning LOX-1 in atherosclerosis, metabolic diseases and cancer. One of them involves NF-kB, an oncogenic protein that regulates the transcription of several inflammatory genes response. In a model of cellular transformation, the MCF10A ER-Src, inhibition of LOX-1 gene reduces NF-kB activation and the inflammatory and hypoxia pathways, suggesting a mechanistic connection between cellular transformation and atherosclerosis. The remodeling proteins MMP-2 and MMP-9 have been found increased in angiogenesis in atherosclerotic plaque and also in human prostate cancer cells. In this review, we outlined the role of LOX-1 in atherogenesis and tumorigenesis as a potential link in these diseases, suggesting that LOX-1 inhibition could represent a promising strategy in the treatment of atherosclerosis and tumors.
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Affiliation(s)
- Silvana Balzan
- Institute of Clinical Physiology, CNR, Via Moruzzi 1, Pisa 56124, Italy.
| | - Valter Lubrano
- Fondazione CNR/Regione Toscana G. Monasterio, Via Moruzzi 1, Pisa 56124, Italy
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Li SW, Guo Y, He Y, Sun X, Zhao HJ, Wang Y, Wang YJ, Xing MW. Assessment of arsenic trioxide toxicity on cock muscular tissue: alterations of oxidative damage parameters, inflammatory cytokines and heat shock proteins. ECOTOXICOLOGY (LONDON, ENGLAND) 2017; 26:1078-1088. [PMID: 28755286 DOI: 10.1007/s10646-017-1835-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/05/2017] [Indexed: 06/07/2023]
Abstract
To evaluate the toxicity of arsenic trioxide (As2O3) in the muscular tissues (wing, thigh and pectoral) of birds, 72 one-day-old Hy-line cocks were selected and randomly divided into four groups. They were fed either a commercial diet or an arsenic-supplemented diet containing 7.5, 15 or 30 mg/kg As2O3. The experiment lasted for 90 days and the samples of muscular tissues were collected at 30, 60 and 90 days. The results showed that As2O3 exposure significantly lowered the activities of antioxidant enzymes (catalase (CAT), glutathione peroxidase (GSH-Px)) and inhibition ability of hydroxyl radicals (OH) and increased the malondialdehyde (MDA) contents. Furthermore, the mRNA levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), prostaglandin E synthase (PTGEs)) and heat shock proteins (HSPs) in muscular tissue were significantly upregulated in the As2O3 exposure groups. The results indicated that As2O3 exposure resulted in oxidative damage, induced the inflammatory response, and influenced the mRNA levels of HSPs in muscular tissue of cocks. Additionally, the results suggested that HSPs possibly resisted due to the As2O3 exposure-induced oxidative stress and inflammatory response, which provided a favorable environment and played protective roles in the muscular tissues of cocks. The information presented in this study is helpful to understand the mechanism of As2O3 toxicity in bird muscular tissues.
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Affiliation(s)
- Si-Wen Li
- College of Wildlife Resources, Northeast Forestry University, Heilongjiang Province, Harbin, 150040, China
| | - Ying Guo
- College of Wildlife Resources, Northeast Forestry University, Heilongjiang Province, Harbin, 150040, China
| | - Ying He
- College of Wildlife Resources, Northeast Forestry University, Heilongjiang Province, Harbin, 150040, China
| | - Xiao Sun
- College of Wildlife Resources, Northeast Forestry University, Heilongjiang Province, Harbin, 150040, China
| | - Hong-Jing Zhao
- College of Wildlife Resources, Northeast Forestry University, Heilongjiang Province, Harbin, 150040, China
| | - Yu Wang
- College of Wildlife Resources, Northeast Forestry University, Heilongjiang Province, Harbin, 150040, China
| | - Ya-Jun Wang
- College of Wildlife Resources, Northeast Forestry University, Heilongjiang Province, Harbin, 150040, China.
| | - Ming-Wei Xing
- College of Wildlife Resources, Northeast Forestry University, Heilongjiang Province, Harbin, 150040, China.
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15
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Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach. Int J Mol Sci 2017; 18:ijms18091978. [PMID: 28914774 PMCID: PMC5618627 DOI: 10.3390/ijms18091978] [Citation(s) in RCA: 319] [Impact Index Per Article: 39.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 09/01/2017] [Accepted: 09/05/2017] [Indexed: 12/12/2022] Open
Abstract
Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of "client" proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail.
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Ge H, He X, Guo L, Yang X. Clinicopathological significance of HSP27 in gastric cancer: a meta-analysis. Onco Targets Ther 2017; 10:4543-4551. [PMID: 28979146 PMCID: PMC5602475 DOI: 10.2147/ott.s146590] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Many studies have provided increasing evidence to demonstrate that HSP27 has been involved in the development of gastric cancer; however, they all include few patients and the results remain controversial. Hence, we conducted a meta-analysis to evaluate correlations between HSP27 and the clinicopathological characteristics of gastric cancer. Methods An electronic search for relevant articles was conducted in PubMed, Cochrane Library, Web of Science, EMBASE database, Chinese CNKI, and Wan Fang. Data on the relationship between HSP27 expression and lymph node metastasis, serosal invasion, gender, tumor size, differentiation, and TNM stage were extracted. Pooled odds ratios and 95% confidence intervals were estimated by forest plot. Results The pooled analyses suggested that HSP27 expression was significantly associated with the incidence of gastric cancer. However, HSP27 expression had no significant relationship with lymph node metastasis, serosal invasion, gender, tumor size, differentiation, and TNM stage. Conclusion Our meta-analysis demonstrated that HSP27 may play vital roles in tumorigenesis and deterioration of gastric cancer. However, further high-quality studies are needed to provide more reliable evidence.
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Affiliation(s)
- Hua Ge
- Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, People's Republic of China
| | - Xueyan He
- Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, People's Republic of China
| | - Lingfei Guo
- Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, People's Republic of China
| | - Xianzhi Yang
- Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, People's Republic of China
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Li C, Zhang J, Wu H, Li L, Yang C, Song S, Peng P, Shao M, Zhang M, Zhao J, Zhao R, Wu W, Ruan Y, Wang L, Gu J. Lectin-like oxidized low-density lipoprotein receptor-1 facilitates metastasis of gastric cancer through driving epithelial-mesenchymal transition and PI3K/Akt/GSK3β activation. Sci Rep 2017; 7:45275. [PMID: 28345638 PMCID: PMC5366889 DOI: 10.1038/srep45275] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 02/23/2017] [Indexed: 12/23/2022] Open
Abstract
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a pattern recognition receptor that plays a critical role in vascular diseases and host immune response. Recently, our research discovered that LOX-1 could facilitate the uptake of dying cells and cross-presentation of cellular antigen via binding with heat shock proteins, which have a close relationship with gastric neoplasia. Therefore, we speculated that LOX-1 may serve as an oncogene in gastric cancer (GC) development and progression. In this study, through immunohistochemistry staining assay and cancer-related databases, we found that LOX-1 expression was up-regulated in GC tissues and correlated with a poor prognosis in GC patients. The expression of LOX-1 was an independent prognostic factor for OS in GC patients, and the incorporation of LOX-1 with TNM stage is more accurate for predicting prognosis. Additionally, in vitro study by transwell assay and western blot analysis confirmed that LOX-1 could promote the migration and invasion of GC cells by driving epithelial-mesenchymal transition and PI3K/Akt/GSK3β activation. Taken together, we first explored the expression profiles, clinical significance and biological function of LOX-1 in GC, and these data suggest that LOX-1 may represent a promising prognostic biomarker for GC and offer a novel molecular target for GC therapies.
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Affiliation(s)
- Can Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Jie Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Hao Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Lili Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Caiting Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Shushu Song
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Peike Peng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Miaomiao Shao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Mingming Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Junjie Zhao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ran Zhao
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Weicheng Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Yuanyuan Ruan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Lan Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
| | - Jianxin Gu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R.China
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Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat Shock Proteins and Cancer. Trends Pharmacol Sci 2016; 38:226-256. [PMID: 28012700 DOI: 10.1016/j.tips.2016.11.009] [Citation(s) in RCA: 457] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/23/2016] [Accepted: 11/11/2016] [Indexed: 12/21/2022]
Abstract
Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation whose expression is induced by heat shock or other stressors. The major groups are classified based on their molecular weights and include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSPs. HSPs play a significant role in cellular proliferation, differentiation, and carcinogenesis. In this article we comprehensively review the roles of major HSPs in cancer biology and pharmacology. HSPs are thought to play significant roles in the molecular mechanisms leading to cancer development and metastasis. HSPs may also have potential clinical uses as biomarkers for cancer diagnosis, for assessing disease progression, or as therapeutic targets for cancer therapy.
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Affiliation(s)
- Jianming Wu
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Tuoen Liu
- Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, WV 24901, USA.
| | - Zechary Rios
- University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA
| | - Qibing Mei
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xiukun Lin
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Shousong Cao
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.
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The cytomegalovirus protein UL138 induces apoptosis of gastric cancer cells by binding to heat shock protein 70. Oncotarget 2016; 7:5630-45. [PMID: 26735338 PMCID: PMC4868710 DOI: 10.18632/oncotarget.6800] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 12/05/2015] [Indexed: 01/16/2023] Open
Abstract
It has been hypothesized that human cytomegalovirus (HCMV) could act as a tumor promoter and play an “oncomodulatory” role in the neoplastic process of several human malignancies. However, we demonstrate for the first time that UL138, a HCMV latency-associated gene, could act as a tumor inhibitor in gastric cancer (GC). The expression of UL138 is down-regulated in HCMV positive gastric adenocarcinoma tissues, especially in poorly or none differentiated tumors. Overexpression of UL138 in several human GC cell lines inhibits cell viability and induces apoptosis, in association with the reduction of an anti-apoptotic Bcl-2 protein and the induction of cleaved caspase-3 and caspase-9. Moreover, protein array analysis reveals that UL138 interacts with a chaperone protein, heat shock protein 70 (HSP70). This interaction is confirmed by immunoprecipitation and immunostaining in situ in GC cell lines. In addition, this UL138-mediated cancer cell death could efficiently lead to suppression of human tumor growth in a xenograft animal model of GC. In conclusion, these results uncover a previously unknown role of the cytomegalovirus protein UL138 in inducing GC cells apoptosis, which might imply a general mechanism that viral proteins inhibit cancer growth in interactions with both chaperones and apoptosis-related proteins. Our findings might provide a potential target for new therapeutic strategies of GC treatment.
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Iqbal MK, Zargar MA, Mudassar S, Lone GN, Yaseen SB, Andrabi KI. Expression Profiling and Cellular Localization of Stress Responsive Proteins in Squamous Cell Carcinoma of Human Esophagus. Cancer Invest 2016; 34:237-45. [PMID: 27351523 DOI: 10.1080/07357907.2016.1178760] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND The ambiguity in relating expression dynamics of stress response proteins with human esophageal squamous cell carcinoma (ESCC) has sidelined the potential of stress proteins as therapeutic targets. This study was an attempt to unequivocally relate the stress protein dynamics with stage and propensity of ESCC. METHODS Surgically resected tumor and adjacent histologically normal tissue from 46 patients with esophageal squamous cell carcinoma were investigated in the present study. Expression of HSPs was analyzed by Western blotting and immunohistochemistry. RESULTS HSP expression was observed in all 46 cases both in adjacent normal and tumor tissues. The expression and the localization of individual HSP showed no significant correlation with depth of invasion, tumor grade, and pathological stage of the tumor. HSP 27 was the most abundant protein followed by HSP 90 and HSP 70. The HSP 27 localized exclusively in the cytoplasm of adjacent normal and tumor cells. HSP 70 showed dispersed expression with predominating nuclear localization in both normal and tumor tissue cells and HSP 90 was localized in cytoplasm of adjacent normal and in nucleus of tumor cells in majority of the cases. CONCLUSION Our data advocate lack of relationship between stress protein expression and the progression of ESCC. The data renew the prospect of anti-HSP drugs as therapeutic resources in light of the possibility that their use would continue to sensitize cancer cells towards drug induced apoptosis for tumor regression.
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Affiliation(s)
| | | | - Syed Mudassar
- b Department of Biochemistry , Sher-i-Kashmir Institute of Medical Sciences , Srinagar , India
| | - Ghulam Nabi Lone
- c Department of Cardio Vascular Thoracic Surgery , Sher-i-Kashmir Institute of Medical Sciences , Srinagar , India
| | - Syed Besina Yaseen
- d Department of Pathology , Sher-i-Kashmir Institute of Medical Sciences , Srinagar , India
| | - Khurshid Iqbal Andrabi
- e Department of Biotechnology , Science Block , University of Kashmir , Srinagar , India
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21
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Liu T, Ye YW, Zhu AL, Yang Z, Fu Y, Wei CQ, Liu Q, Zhao CL, Wang GJ, Zhang XF. Hyperthermia combined with 5-fluorouracil promoted apoptosis and enhanced thermotolerance in human gastric cancer cell line SGC-7901. Onco Targets Ther 2015; 8:1265-70. [PMID: 26064061 PMCID: PMC4455869 DOI: 10.2147/ott.s78514] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
This study was designed to investigate the proliferation inhibition and apoptosis-promoting effect under hyperthermia and chemotherapy treatment, at cellular level. Human gastric cancer cell line SGC-7901 was cultivated with 5-fluorouracil at different temperatures. Cell proliferation and apoptosis were determined, and expression of Bcl-2 and HSP70 was measured at different treatments. Cell survival rates and inhibition rates in chemotherapy group, thermotherapy group, and thermo-chemotherapy group were drastically lower than the control group (P<0.05). For tumor cells in the thermo-chemotherapy group, survival rates and inhibition rates at three different temperatures were all significantly lower than those in chemotherapy group and thermotherapy group (P<0.05). 5-Fluorouracil induced apoptosis of SGC-7901 cells with a strong temperature dependence, which increased gradually with increase in temperature. At 37°C and 43°C there were significant differences between the thermotherapy group and chemotherapy group and between the thermo-chemotherapy group and thermotherapy group (P<0.01). The expression of Bcl-2 was downregulated and HSP70 was upregulated, with increase in temperature in all groups. Cell apoptosis was not significant at 46°C (P>0.05), which was probably due to thermotolerance caused by HSP70 accumulation. These results suggested that hyperthermia combined with 5-fluorouracil had a synergistic effect in promoting apoptosis and enhancing thermotolerance in gastric cancer cell line SGC-7901.
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Affiliation(s)
- Tao Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Yan-Wei Ye
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - A-Li Zhu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Zhen Yang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Yang Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Chong-Qing Wei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Qi Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Chun-Lin Zhao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Guo-Jun Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Xie-Fu Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
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Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer. Exp Mol Pathol 2015; 98:338-45. [PMID: 25805104 DOI: 10.1016/j.yexmp.2015.03.029] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 03/20/2015] [Indexed: 12/16/2022]
Abstract
Genes associated with protein folding have been found to have certain prognostic significance in a subset of cancers. The aim of this study is to evaluate the clinical impact of DNAJC12 expression in patients with rectal cancers receiving neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery. Through data mining from a public transcriptomic dataset of rectal cancer focusing on genes associated with protein folding, we found that DNAJC12, a member of the HSP40/DNAJ family, was the most significant such gene correlated with the CCRT response. We further evaluated the expression of DNAJC12 by immunohistochemistry in the pre-treatment tumor specimens from 172 patients with rectal cancers. From this set, we statistically analyzed the association of DNAJC12 expression with various clinicopathological factors, tumor regression grade, overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS). High expression of DNAJC12 was significantly associated with advanced pre- and post-treatment tumor status (P<0.001), advanced pre- and post-treatment nodal status (P<0.001), increased vascular invasion (P=0.015), increased perineural invasion (P=0.023) and lower tumor regression grade (P=0.009). More importantly, high expression of DNAJC12 was found to be correlated with poor prognosis for OS (P=0.0012), DFS (P<0.0001) and LRFS (P=0.0001). In multivariate analysis, DNAJC12 overexpression still emerged as an independent prognosticator for shorter OS (P=0.040), DFS (P<0.001) and LRFS (P=0.016). The data indicate that DNAJC12 overexpression acts as a negative predictive factor for the response to neoadjuvant CCRT and was significantly associated with shorter survival in patients with rectal cancers receiving neoadjuvant CCRT followed by surgery.
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Zhang NS, Li HY, Liu JS, Yang WD. Gene expression profiles in zebrafish (Danio rerio) liver after acute exposure to okadaic acid. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2014; 37:791-802. [PMID: 24637248 DOI: 10.1016/j.etap.2014.02.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 02/05/2014] [Accepted: 02/06/2014] [Indexed: 06/03/2023]
Abstract
Okadaic acid (OA), a main component of diarrheic shellfish poisoning (DSP) toxins, is a strong and specific inhibitor of the serine/threonine protein phosphatases PP1 and PP2A. However, not all of the OA-induced effects can be explained by this phosphatase inhibition, and controversial results on OA are increasing. To provide clues on potential mechanisms of OA other than phosphatase inhibition, here, acute toxicity of OA was evaluated in zebrafish, and changes in gene expression in zebrafish liver tissues upon exposure to OA were observed by microarray. The i.p. ED50 (6 h) of OA on zebrafish was 1.54 μg OA/g body weight (bw). Among the genes analyzed on the zebrafish array, 55 genes were significantly up-regulated and 36 down-regulated in the fish liver tissue upon exposure to 0.176 μg OA/g bw (low-dose group, LD) compared with the low ethanol control (LE). However, there were no obvious functional clusters for them. On the contrary, fish exposure to 1.760 μg OA/g bw (high-dose group, HD) yielded a great number of differential expressed genes (700 up and 285 down) compared with high ethanol control (HE), which clustered in several functional terms such as p53 signaling pathway, Wnt signaling pathway, glutathione metabolism and protein processing in endoplasmic reticulum, etc. These genes were involved in protein phosphatase activity, translation factor activity, heat shock protein binding, as well as transmembrane transporter activity. Our findings may give some useful information on the pathways of OA-induced injury in fish.
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Affiliation(s)
- Nai-sheng Zhang
- College of Life Science and Technology, Jinan University, Guangzhou 510632, PR China; Wageningen University and Research Centre, Centre for Water and Climate, Alterra, PO Box 47, 6700AA Wageningen, The Netherlands
| | - Hong-ye Li
- College of Life Science and Technology, Jinan University, Guangzhou 510632, PR China; Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, P. R. China
| | - Jie-sheng Liu
- College of Life Science and Technology, Jinan University, Guangzhou 510632, PR China; Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, P. R. China
| | - Wei-dong Yang
- College of Life Science and Technology, Jinan University, Guangzhou 510632, PR China; Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, P. R. China.
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Lee HW, Lee EH, Kim SH, Roh MS, Jung SB, Choi YC. Heat shock protein 70 (HSP70) expression is associated with poor prognosis in intestinal type gastric cancer. Virchows Arch 2013; 463:489-95. [PMID: 23913168 DOI: 10.1007/s00428-013-1461-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 06/20/2013] [Accepted: 07/16/2013] [Indexed: 12/31/2022]
Abstract
Heat shock protein 70 (HSP70) is a molecular chaperone which plays an important role in cellular protection against various stressful stimuli and in the regulation of cellular growth and apoptosis. This study was conducted in gastric carcinoma (GC) to assess correlations of HSP70 expression with clinicopathological parameters and overall survival (OS). Tissue microarray blocks were constructed from 172 GCs and immunohistochemically stained for HSP70. Low HSP70 expression was found in 122 GCs (71 %), whereas 50 (29 %) had high expression. HSP70 expression was higher in tumours in the cardia (p = 0.008), with non-signet ring cell histology (p < 0.001), of intestinal type (p = 0.045) and of higher pathological T stage (p = 0.026). When considering the cohort as a whole, HSP70 expression did not correlate with OS (p = 0.092). In intestinal type carcinomas, however, high HSP70 expression significantly correlated with worse OS (p = 0.034). These results suggest that HSP70 expression might be an unfavourable prognostic factor in patients with GC, especially of intestinal type.
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Affiliation(s)
- Hyoun Wook Lee
- Department of Pathology, Samsung Changwon Hospital, School of Medicine, Sungkyunkwan University, Changwon, South Korea
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25
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Kang Y, Jung WY, Lee H, Jung W, Lee E, Shin BK, Kim A, Kim HK, Kim BH. Prognostic significance of heat shock protein 70 expression in early gastric carcinoma. KOREAN JOURNAL OF PATHOLOGY 2013; 47:219-26. [PMID: 23837014 PMCID: PMC3701817 DOI: 10.4132/koreanjpathol.2013.47.3.219] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 04/24/2013] [Accepted: 04/25/2013] [Indexed: 01/29/2023]
Abstract
Background Overexpression of heat shock protein 70 (HSP70) has been observed in many types of cancer including gastric adenocarcinomas, although the exact role of HSP70 in carcinogenesis remains unclear. Methods The study analyzed a total of 458 radical gastrectomy specimens which were immunohistochemically stained with HSP70, p53, and Ki-67 antibodies. Results The study determined that the expression of HSP70 was significantly increased in early gastric cancer (EGC) compared to advanced gastric cancer (p<0.001). The HSP70 expression was correlated with well-differentiated tumor type, intestinal type of Lauren classification and the lower pT and pN stage. Negative expression of Ki-67 and p53 expression was associated with poor prognosis. The study did not find any correlation between HSP70 and p53 expression. The study determined that HSP70 expression in the EGC subgroup was associated with a poor prognosis (p=0.009), as well as negative Ki-67 expression (p=0.006), but was not associated with p53. Based on multivariate analysis, HSP70 expression (p=0.024), negative expression of Ki-67, invasion depth and lymph node metastasis were determined to be independent prognostic markers. Conclusions HSP70 is expressed in the early stages of gastric adenocarcinoma. In EGC, HSP70 is a poor independent prognostic marker and is correlated with a low proliferation index.
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Affiliation(s)
- Youngran Kang
- Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
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26
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Zhang HC, Shi R, Li J, Li XH, Li JX, Yang MJ. Effect of astragalus and Panax notoginseng on expression of heat shock protein 70 and GAF in atrophic gastritis in rats. Shijie Huaren Xiaohua Zazhi 2013; 21:559-566. [DOI: 10.11569/wcjd.v21.i7.559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effect of astragalus, Panax notoginseng and their mixture on expression of heat shock protein 70 (HSP70) and GAF in atrophic gastritis in rats.
METHODS: Fifty-four healthy male Wistar rats were randomly divided into six groups: control group, model group, teprenone group, astragalus group, Panax notoginseng group and astragalus plus Panax notoginseng group. Atrophic gastritis was induced by implanting a pylorus spring and intragastrically administering hot salty starch paste. The control and model groups were given normal saline (2 mL) daily, while other groups were infused with water decoction of astragalus containing crude drug 3.5 g/(kg·d), the Panax notoginseng powder containing crude drug 0.7 g/(kg·d), Panax notoginseng powder and astragalus water decoction, and teprenone water suspension containing teprenone 200 mg/(kg·d) for one month by gavage, respectively. The expression of heat shock protein 70 and GAF in the rat gastric mucosa was measured using quantum dot immunofluorescence histochemical technology.
RESULTS: HSP70 protein expression in the astragalus, Panax notoginseng, astragalus plus Panax notoginseng and teprenone groups was significantly increased (all P < 0.05) compared to the model group. The expression of GAF in the astragalus, Panax notoginseng, astragalus plus Panax notoginseng and teprenone groups was also increased significantly compared to the model group (all P < 0.01). Although the expression of HSP70 in the astragalus group was higher than that in the Panax notoginseng group (P < 0.05), there was no significant difference in the expression of GAF between the two groups (P > 0.05).
CONCLUSION: Astragalus, Panax notoginseng and their combination can improve mucosal atrophy in rats with atrophic gastritis by increasing GAF and HSP70 expression. GAF and HSP70 may be potential therapeutic targets for atrophic gastritis.
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Calderwood SK. Molecular cochaperones: tumor growth and cancer treatment. SCIENTIFICA 2013; 2013:217513. [PMID: 24278769 PMCID: PMC3820307 DOI: 10.1155/2013/217513] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 04/01/2013] [Indexed: 05/12/2023]
Abstract
Molecular chaperones play important roles in all cellular organisms by maintaining the proteome in an optimally folded state. They appear to be at a premium in cancer cells whose evolution along the malignant pathways requires the fostering of cohorts of mutant proteins that are employed to overcome tumor suppressive regulation. To function at significant rates in cells, HSPs interact with cochaperones, proteins that assist in catalyzing individual steps in molecular chaperoning as well as in posttranslational modification and intracellular localization. We review current knowledge regarding the roles of chaperones such as heat shock protein 90 (Hsp90) and Hsp70 and their cochaperones in cancer. Cochaperones are potential targets for cancer therapy in themselves and can be used to assess the likely prognosis of individual malignancies. Hsp70 cochaperones Bag1, Bag3, and Hop play significant roles in the etiology of some cancers as do Hsp90 cochaperones Aha1, p23, Cdc37, and FKBP1. Others such as the J domain protein family, HspBP1, TTC4, and FKBPL appear to be associated with more benign tumor phenotypes. The key importance of cochaperones for many pathways of protein folding in cancer suggests high promise for the future development of novel pharmaceutical agents.
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Affiliation(s)
- Stuart K. Calderwood
- Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA
- *Stuart K. Calderwood:
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28
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Wang X, Wang Q, Lin H, Li S, Sun L, Yang Y. HSP72 and gp96 in gastroenterological cancers. Clin Chim Acta 2012; 417:73-9. [PMID: 23266770 DOI: 10.1016/j.cca.2012.12.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 12/14/2012] [Accepted: 12/15/2012] [Indexed: 11/30/2022]
Abstract
Heat shock protein 72 (HSP72) and glycoprotein 96 (gp96) are highly expressed in cancer tissues. Recent studies indicate the possible roles of HSP72 and gp96 in the development and progression of gastrointestinal carcinomas but detailed mechanisms are still ambiguous. Human esophageal cancer, gastric cancer, colon cancer and liver cancer are common gastrointestinal malignant carcinomas in the world. The studies indicated that there existed a significant correlation between the expression of HSP72, gp96 and the development and progression of digestive carcinomas. HSP72 and gp96 expression were significantly associated with the presence of tumor infiltration, lymph node and remote metastasis. Interestingly, studies have found that HSP72 chaperoned alpha-fetoprotein (AFP), HBx in hepatocellular carcinoma, and CD44 in colonic carcinomas. The further researches demonstrated that HSP72-AFP or gp96-AFP recombined vaccine could elicit specific anti-tumor immunity. The high-level expression of HSP72 and gp96 may be not only used as diagnostic or prognostic markers for gastrointestinal carcinomas but also as better immunotherapeutic vaccines in the cancers.
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Affiliation(s)
- Xiaoping Wang
- Key Laboratory of Molecular Biology and Pathology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, PR China.
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29
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Smith RW, Wang J, Schültke E, Seymour CB, Bräuer-Krisch E, Laissue JA, Blattmann H, Mothersill CE. Proteomic changes in the rat brain induced by homogenous irradiation and by the bystander effect resulting from high energy synchrotron X-ray microbeams. Int J Radiat Biol 2012; 89:118-27. [DOI: 10.3109/09553002.2013.732252] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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30
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He B, Wang X, Shi HS, Xiao WJ, Zhang J, Mu B, Mao YQ, Wang W, Wang YS. Quercetin Liposome Sensitizes Colon Carcinoma to Thermotherapy and Thermochemotherapy in Mice Models. Integr Cancer Ther 2012; 12:264-70. [PMID: 22740083 DOI: 10.1177/1534735412446863] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Thermotherapy and thermochemotherapy have been used in clinics to treat patients with malignant diseases, including colon cancer, and their efficacy has been well proved. Heat shock proteins (HSPs), especially Hsp70, play important roles in neutralizing their efficacy. It has been reported that quercetin can suppress cancer by inhibiting the intratumoral expression of Hsp70. This study was designed to investigate whether quercetin could enhance sensitivity to thermotherapy and thermochemotherapy. Soluble quercetin liposome was used in this study. The effects of quercetin were investigated in vitro and in mouse colon cancer models of subcutaneous tumor and peritoneal carcinomatosis. The results showed that quercetin liposome inhibited the upregulation of Hsp70 and enhanced apoptosis induced by hyperthermia and thermochemotherapy. Systemic administration of quercetin liposome can sensitize CT26 cells to thermotherapy and chemothermotherapy. This study suggests that quercetin liposome might be potentially applied for clinical cancer therapy.
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Affiliation(s)
- Bing He
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Xin Wang
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Hua-shan Shi
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
- Department of thoracic oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Wen-jing Xiao
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Jing Zhang
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Bo Mu
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Yong-qiu Mao
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Wei Wang
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Yong-sheng Wang
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
- Department of thoracic oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
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31
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Sterrenberg JN, Blatch GL, Edkins AL. Human DNAJ in cancer and stem cells. Cancer Lett 2011; 312:129-42. [PMID: 21925790 DOI: 10.1016/j.canlet.2011.08.019] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 07/15/2011] [Accepted: 08/17/2011] [Indexed: 12/12/2022]
Abstract
The heat shock protein 40kDa (HSP40/DNAJ) co-chaperones constitute the largest and most diverse sub-group of the heat shock protein (HSP) family. DNAJ are widely accepted as regulators of HSP70 function, but also have roles as co-chaperones for the HSP90 chaperone machine, and a growing number of biological functions that may be independent of either of these chaperones. The DNAJ proteins are differentially expressed in human tissues and demonstrate the capacity to function to both promote and suppress cancer development by acting as chaperones for tumour suppressors or oncoproteins. We review the current literature on the function and expression of DNAJ in cancer, stem cells and cancer stem cells. Combining data from gene expression, proteomics and studies in other systems, we propose that DNAJ will be key regulators of cancer, stem cell and possibly cancer stem cell function. The diversity of DNAJ and their assorted roles in a range of biological functions means that selected DNAJ, provided there is limited redundancy and that a specific link to malignancy can be established, may yet provide an attractive target for specific and selective drug design for the development of anti-cancer treatments.
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Affiliation(s)
- Jason N Sterrenberg
- Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown South Africa
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32
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Khalil AA, Kabapy NF, Deraz SF, Smith C. Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets? Biochim Biophys Acta Rev Cancer 2011; 1816:89-104. [PMID: 21605630 DOI: 10.1016/j.bbcan.2011.05.001] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2010] [Revised: 05/04/2011] [Accepted: 05/06/2011] [Indexed: 02/08/2023]
Abstract
Heat shock proteins (HSP) are a family of proteins induced in cells exposed to different insults. This induction of HSPs allows cells to survive stress conditions. Mammalian HSPs have been classified into six families according to their molecular size: HSP100, HSP90, HSP70, HSP60, HSP40 and small HSPs (15 to 30kDa) including HSP27. These proteins act as molecular chaperones either helping in the refolding of misfolded proteins or assisting in their elimination if they become irreversibly damaged. In recent years, proteomic studies have characterized several different HSPs in various tumor types which may be putative clinical biomarkers or molecular targets for cancer therapy. This has led to the development of a series of molecules capable of inhibiting HSPs. Numerous studies speculated that over-expression of HSP is in part responsible for resistance to many anti-tumor agents and chemotherapeutics. Hence, from a pharmacological point of view, the co-administration of HSP inhibitors together with other anti-tumor agents is of major importance in overcoming therapeutic resistance. In this review, we provide an overview of the current status of HSPs in autoimmune, cardiovascular, and neurodegenerative diseases with special emphasis on cancer.
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Affiliation(s)
- Ashraf A Khalil
- Department of Protein Technology, Institute of Genetic Engineering and Biotechnology, Mubarak City for Scientific Research, New Borg Elarab, Alexandria, Egypt.
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Cui XB, Yu ZY, Wang W, Zheng YQ, Liu W, Li LX. Co-Inhibition of HSP70/HSP90 Synergistically Sensitizes Nasopharyngeal Carcinoma Cells to Thermotherapy. Integr Cancer Ther 2011; 11:61-7. [PMID: 21498475 DOI: 10.1177/1534735411399900] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The upregulation of both HSP70 and HSP90 frequently compromises the effects of thermotherapy. The co-inhibition of HSP70/HSP90 may be preferable to enhance the effects of thermotherapy on nasopharyngeal carcinoma cells. The changes of HSP70 and HSP90 were detected after thermotherapy in human nasopharyngeal cancer cell HNE1. 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) and quercetin were used to inhibit the activity of HSP90 and HSP70. The enhanced effects were evaluated in vitro and in vivo. Both HSP70 and HSP90 were upregulated promptly in HNE1 after thermotherapy. Single inhibition of HSP70 resulted in overexpression and delayed descent of HSP90. The co-inhibition of HSP70/HSP90 with quercetin plus 17-DMAG significantly increased apoptosis in hyperthermia-treated HNE1 cells both in vitro and in vivo. The co-inhibition of HSP70/HSP90 synergistically sensitizes nasopharyngeal carcinoma cells to hyperthermia.
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Affiliation(s)
- Xiao-bo Cui
- Inner Mongolia Medical College Hospital, Hohhot, Inner Mongolia, People’s Republic of China
| | - Zhao-yan Yu
- Inner Mongolia Medical College Hospital, Hohhot, Inner Mongolia, People’s Republic of China
| | - Wei Wang
- Inner Mongolia Medical College Hospital, Hohhot, Inner Mongolia, People’s Republic of China
| | - Yan-qiu Zheng
- Inner Mongolia Medical College Hospital, Hohhot, Inner Mongolia, People’s Republic of China
| | - Wei Liu
- Inner Mongolia Medical College Hospital, Hohhot, Inner Mongolia, People’s Republic of China
| | - Ling-xiang Li
- Inner Mongolia Medical College Hospital, Hohhot, Inner Mongolia, People’s Republic of China
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Carrasco V, Canfrán S, Rodríguez-Franco F, Benito A, Sáinz A, Rodríguez-Bertos A. Canine gastric carcinoma: immunohistochemical expression of cell cycle proteins (p53, p21, and p16) and heat shock proteins (Hsp27 and Hsp70). Vet Pathol 2010; 48:322-9. [PMID: 20587688 DOI: 10.1177/0300985810375050] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Immunohistochemical staining for cell cycle proteins and heat shock proteins was performed on 17 canine gastric carcinomas. The immunoexpression of p53, p21, p16, Hsp27, and Hsp70 was investigated. A study was conducted to determine the histological type and parameters related to tumor malignancy. Possible associations and trends were assessed between the immunoexpression of each protein and tumor type as well as specific parameters of malignancy. High intratumor frequency of cellular p53 immunostaining was observed (61.96% average), but lower frequencies of p21 and p16 expression were present (34.65% and 10.41%, respectively). The p53 overexpression was associated with tumor infiltration (P = .0258). Expression of p21 was lower in undifferentiated carcinomas, and the loss of expression was associated with histopathological parameters characteristic of a poor prognosis such as lymphatic vessel invasion (P = .0258). The lack of p16 immunoreactivity was related to histopathological characteristics of malignancy such as the presence of evident and multiple nucleoli (P = .0475). In contrast, deep tumor infiltration was observed in those carcinomas with a high p16 index (P = .0475). Hsp70 appeared to be overexpressed in all gastric neoplasms included in this study. This is in contrast to Hsp27, because a group of tumors showed complete lack of Hsp27 immunoexpression, whereas the others displayed extensive Hsp27 immunostaining. The differences in Hsp27 did not correlate with any of the histopathological parameters, but Hsp27 immunoexpression was higher in the undifferentiated carcinoma. No significant differences in the expression of the proteins were found in canine gastric carcinomas according to their histological type. These findings may be useful for establishing a prognosis for canine gastric carcinoma.
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Affiliation(s)
- V Carrasco
- Department of Animal Medicine and Surgery, Veterinary Teaching Hospital, Complutense University of Madrid, Madrid, Spain
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35
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Yang X, He H, Yang W, Song T, Guo C, Zheng X, Liu Q. Effects of HSP70 antisense oligonucleotide on the proliferation and apoptosis of human hepatocellular carcinoma cells. ACTA ACUST UNITED AC 2010; 30:337-43. [PMID: 20556578 DOI: 10.1007/s11596-010-0353-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Indexed: 12/19/2022]
Abstract
The study investigated the effects of heat shock protein 70 (HSP70) antisense oligonucleotide (ASODN) on the proliferation and apoptosis of a human hepatocellular carcinoma cell line (SMMC-7721 cells) in vitro. HSP70 oligonucleotide was transfected into SMMC-7721 cells by the mediation of Sofast transfection reagent. Inhibition rate of SMMC-7721 cells was determined by using MTT method. Apoptosis rate and cell cycle distribution were measured by flow cytometry. Immunocytochemistry staining was used to observe the expression of HSP70, Bcl-2 and Bax. The results showed that HSP70 ASODN at various concentrations could significantly inhibit the growth of SMMC-7721 cells, and the inhibition effect peaked 48 h after transfection with 400-nmol/L HSP70 ASODN. Cytometric analysis showed the apoptotic rate was increased in a dose- and time-dependent manner in the HSP70 ASODN-treated cells. The percentage of cells in the G2/M and S phases was significantly decreased and that in the G0/G1 phase increased as the HSP70 ASODN concentration was elevated and the exposure time prolonged. Immunocytochemistry showed that treatment of SMMC-7721 cells with HSP70 ASODN resulted in decreased expressions of HSP70 and Bcl-2 proteins, and an increased expression of Bax protein. It was concluded that the HSP70 ASODN can inhibit the growth of the SMMC-7721 cells and increase cell apoptosis by down-regulating the expression of HSP70. HSP70 ASODN holds promise for the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Xue Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, 710061, China.
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Partida-Rodríguez O, Torres J, Flores-Luna L, Camorlinga M, Nieves-Ramírez M, Lazcano E, Perez-Rodríguez M. Polymorphisms in TNF and HSP-70 show a significant association with gastric cancer and duodenal ulcer. Int J Cancer 2010; 126:1861-1868. [PMID: 19626584 DOI: 10.1002/ijc.24773] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Tumour Necrosis Factor (TNF) and Heat Shock Protein 70 (HSP70) are important molecules in inflammatory, infectious and tumoral processes. The genes codifying these molecules are polymorphic and certain alleles have been associated with susceptibility to disease. Gastric cancer is associated with an Helicobacter pylori-induced chronic inflammatory response. The aim of this work was to analyze whether polymorphisms in inflammation-related genes are associated with the development of gastric cancer. We studied 447 Mexican adult patients including 228 with non-atrophic gastritis, 98 with intestinal metaplasia, 63 with gastric cancer and 58 with duodenal ulcer, and 132 asymptomatic individuals as well. DNA from peripheral white blood cells was typed for the Single Nucleotide Polymorphisms (SNPs) -308 of TNF-alpha, +252 of TNF-beta, +190 of HSP70-1, +1267 of HSP70-2 and +2437 of HSP70-HOM. Compared with the asymptomatic group, we found a significant association of TNF-beta*A and HSP70-1*C alleles with gastric cancer (OR 5.69 and 3.76, respectively) and HSP70-1*C with duodenal ulcer (OR 3.08). Genotype TNF-beta G/G showed a significant gene-dose effect with gastric cancer (OR 0.09); whereas HSP70-1 C/G showed significant association with both, gastric cancer (OR 13.31) and duodenal ulcer (OR 16.19). Polymorphisms in TNF and HSP70 showed a significant severity-dose-response as risk markers from preneoplastic lesions to gastric cancer in Mexican population, probably because of their association with an intense and sustained inflammatory response.
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Affiliation(s)
| | - Javier Torres
- Infectious Diseases Research Unity, Pediatric Hospital, CMN S-XXI, IMSS, Mexico City CP 06720, Mexico
| | | | - Margarita Camorlinga
- Infectious Diseases Research Unity, Pediatric Hospital, CMN S-XXI, IMSS, Mexico City CP 06720, Mexico
| | - Miriam Nieves-Ramírez
- Immunology Research Unity, Pediatric Hospital, CMN S-XXI, IMSS, Mexico City CP 06720, Mexico
| | - Eduardo Lazcano
- Instituto Nacional de Salud Pública, Cuernavaca, Morelos CP 62100, Mexico
| | - Martha Perez-Rodríguez
- Immunology Research Unity, Pediatric Hospital, CMN S-XXI, IMSS, Mexico City CP 06720, Mexico
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Correlation between clinicopathology and expression of heat shock protein 72 and glycoprotein 96 in human esophageal squamous cell carcinoma. Clin Dev Immunol 2010; 2010:212537. [PMID: 20300187 PMCID: PMC2836527 DOI: 10.1155/2010/212537] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2009] [Revised: 11/30/2009] [Accepted: 01/21/2010] [Indexed: 01/30/2023]
Abstract
Heat shock protein 72 (HSP72) and glycoprotein 96 (gp96) are highly expressed in cancer tissues. Recent studies indicate the possible roles of HSP72 and gp96 in the development and progression of gastrointestinal carcinomas but detailed information is still ambiguous. We investigated the correlation between clinicopathology and expression of HSP72 and gp96 in human esophageal squamous cell carcinoma. The expression of HSP72 and gp96 was studied in 120 human esophageal squamous cell carcinomas with or without metastasis as well as in mucous membrane adjacent to cancers by way of immunohistochemistry. HSP72 immunoreactivities were detected in 112 of 120 primary tumors (93.3%) and in 30 of 120 mucous membranes adjacent to cancers (25.0%). Gp96 detected in esophageal squamous cell carcinoma and inmucous membrane adjacent to cancer was 85.0% and 20.0%, respectively. Both HSP72 and gp96 stained in cytoplasm. HSP72 and gp96 expression in esophageal squamous cell carcinomas withmetastasis was significantly higher than those with nonmetastasis (P < .05). The results indicate that there exists a significant correlation between the expression of HSP72 and gp96 and the progression of esophageal squamous cell carcinomas. HSP72 and gp96 expression were significantly associated with the presence of tumor infiltration, lymph node, and remote metastasis.
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Ki BL, Kyung BP. Comparative proteomic analysis of cancerous and adjacent normal lung tissues. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2010; 56:663-73. [DOI: 10.18097/pbmc20105606663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Lung cancer is the leading cause of cancer-related mortality in industrialized countries. Unfortunately, most lung cancers are found too late for a cure, therefore early detection and treatment is very important. We have applied proteomic analysis by using two-dimensional gel electrophoresis and peptide mass fingerprinting techniques for examination of cancerous and adjacent non-cancerous lung tissues from the same patient. The aim of the study was to find proteins, which could be used as biomarkers for diagnosis and monitoring of this disease. Indeed, we found differences in expression of several proteins, related to various cellular activities, such as, chaperoning (e,g. GRP96, GRP78, HSP27), metabolism and oxidation stress (e.g. L-fucose, GST), cytoskeleton (e.g., tubulin beta 2/3, beta actin), cell adhesion (e.g. annexin A5/3), binding proteins (e.g. 14-3-3 theta) and signal transduction. These changes may be important for progression of carcinogenesis; they may be used as the molecular-support for future diagnostic markers.
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Giaginis C, Daskalopoulou SS, Vgenopoulou S, Sfiniadakis I, Kouraklis G, Theocharis SE. Heat Shock Protein-27, -60 and -90 expression in gastric cancer: association with clinicopathological variables and patient survival. BMC Gastroenterol 2009; 9:14. [PMID: 19203381 PMCID: PMC2644705 DOI: 10.1186/1471-230x-9-14] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2008] [Accepted: 02/09/2009] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Heat shock proteins (HSPs) are ubiquitous, highly conserved proteins across all the species and play essential roles in maintaining protein stability within the cells under normal conditions, while preventing stress-induced cellular damage. HSPs were also overexpressed in various types of cancer, being associated with tumor cell proliferation, differentiation and apoptosis. The aim of the present study was to evaluate the clinical significance of HSP -27, -60, and -90 expression in gastric carcinoma. METHODS HSP -27, -60, and -90 proteins expression was assessed immunohistochemically in tumoral samples of 66 gastric adenocarcinoma patients and was statistically analyzed in relation to various clinicopathological characteristics, tumor proliferative capacity and patients' survival. RESULTS HSP-27, -60, -90 proteins were abundantly expressed in gastric adenocarcinoma cases examined. HSP-27 expression was significantly associated with tumor size (pT, P = 0.026), the presence of organ metastases (pM, P = 0.046) and pStage (P = 0.041), while HSP-27 staining intensity with nodal status (pN, P = 0.042). HSP-60 expression was significantly associated with patients' sex (P = 0.011), while HSP-60 staining intensity with patients' age (P = 0.027) and tumor histopathological grade (P = 0.031). HSP-90 expression was not associated with any of the clinicopathological parameters examined; however, HSP-90 staining intensity was significantly associated with tumor size (pT, P = 0.020). High HSP-90 expression was significantly associated with longer overall survival times in univariate analysis (log-rank test, P = 0.033), being also identified as an independent prognostic factor in multivariate analysis (P = 0.026). CONCLUSION HSP-27, -60, and -90 were associated with certain clinicopathological parameters which are crucial for the management of gastric adenocarcinoma patient. HSP-90 expression may also be an independent prognostic indicator in gastric adenocarcinoma patients.
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Affiliation(s)
- Constantinos Giaginis
- Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens, Greece.
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Xiang TX, Li Y, Jiang Z, Huang AL, Luo C, Zhan B, Wang PL, Tao XH. RNA interference-mediated silencing of the Hsp70 gene inhibits human gastric cancer cell growth and induces apoptosis in vitro and in vivo. TUMORI JOURNAL 2008; 94:539-50. [PMID: 18822691 DOI: 10.1177/030089160809400416] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
AIMS AND BACKGROUND The role of heat shock protein (HSP) 70 in gastric cancer has been extensively examined in many studies for the past decade. It has been demonstrated that over-expression of Hsp70 might play important role in malignant transformation and maintenance of malignant phenotypes. Therefore, silencing the Hsp70 gene could be applicable in molecular therapies of human gastric cancer. Herein, we designed a small interfering RNA targeting Hsp70 to knock down its expression and investigated its effect on cell proliferation and apoptosis in a gastric cancer cell line. METHODS Two plasmids (phsp1-siRNA, phsp2-siRNA), along with a negative control (phsp3-siRNA), were created using a genic recombination technique. BGC823 cell lines were used to perform experiments. Western blotting and RT-PCR were used to detect Hsp70 expression in vitro and in vivo. Cell morphology was observed under light microscope. Cell cycle and apoptosis were analyzed by flow cytometry and acridine orange/ethidium bromide double stain, and cell proliferative activity was measured by alamarblue assay. In all experiments, a negative control served as a baseline measure. RESULTS We successfully constructed phsps-siRNA plasmids and transfected them into BGC823 cells. RT-PCR and western blotting revealed that the expression of Hsp70 was down-regulated in transfection groups compared with the control group. Flow cytometric analysis indicated that less S-phase fraction accumulated in small interfering RNA transfected cells than in parental cells and the cells transfected with empty vector. CONCLUSIONS Our results demonstrated that RNAi against Hsp70 could effectively knock down gene expression, inhibit growth of cancer cells, induce cell cycle arrest and increase cell apoptosis in vitro and in vivo. Hsp70 might serve as a therapeutic target for human gastric cancer.
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Affiliation(s)
- Ting-Xiu Xiang
- Experiment Research Center, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
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Invariant natural killer T cells and immunotherapy of cancer. Clin Immunol 2008; 129:182-94. [PMID: 18783990 DOI: 10.1016/j.clim.2008.07.025] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2007] [Revised: 07/29/2008] [Accepted: 07/29/2008] [Indexed: 11/20/2022]
Abstract
Invariant CD1d restricted natural killer T (iNKT) cells are regulatory cells that express a canonical TCR-Valpha-chain (Valpha24.Jalpha18 in humans and Valpha14.Jalpha18 in mice) which recognizes glycolipid antigens presented by the monomorphic CD1d molecule. They can secrete a wide variety of both pro-inflammatory and anti-inflammatory cytokines very swiftly upon their activation. Evidence for the significance of iNKT cells in human cancer has been ambiguous. Still, the (pre-)clinical findings reviewed here, provide evidence for a distinct contribution of iNKT cells to natural anti-tumor immune responses in humans. Furthermore, clinical phase I studies that are discussed here have revealed that the infusion of cancer patients with ligand-loaded dendritic cells or cultured iNKT cells is well tolerated. We thus underscore the potential of iNKT cell based immunotherapy in conjunction with established modalities such as surgery and radiotherapy, as adjuvant therapy against carcinomas.
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Zhang L, Jiang J, Arellano M, Zhang L, Yan X, Wong DT, Hu S. Quantification of Serum Proteins of Metastatic Oral Cancer Patients Using LC-MS/MS and iTRAQ Labeling. ACTA ACUST UNITED AC 2008; 1:72-78. [PMID: 20485468 DOI: 10.2174/1875039700801010072] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Metastasis is a critical event in oral squamous cell carcinoma (OSCC) progression. In this study, we have performed quantitative analysis of serum proteins from non-metastatic (lymph-node metastasis free) and metastatic OSCC patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with iTRAQ labeling (isobaric tagging for relative and absolute quantitation). To eliminate highly abundant proteins, the serum samples were initially separated by SDS-PAGE and only low abundant protein bands were excised for subsequent in-gel tryptic digestion. The resulting peptides were then extracted from each sample gels and labeled with iTRAQ reagent 114 (control), 116 (non-metastatic) and 117 (metastatic), respectively. Afterwards, the labeled samples were combined and subjected to LC-MS/MS analysis using linear ion trap (LIT) MS with pulsed Q collision induced dissociation (PQD). A total of 64 proteins were identified and quantified by this approach. Our study showed that iTRAQ labeling and LIT-MS with PQD is a valuable approach to quantification of serum proteins. We also demonstrated the presence of differentially expressed serum proteins between non-metastatic and metastatic OSCCs that may be further validated as biomarkers for metastatic OSCC. However, in order to comprehensively quantify low abundant serum proteins, a more efficient approach is needed to deplete highly abundant proteins prior to quantitative serum proteome analysis of OSCC.
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Affiliation(s)
- Lifeng Zhang
- School of Dentistry and Dental Research Institute, University of California, Los Angeles CA 90095, USA
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Wang X, Wang Q, Guo L, Ying X, Zhao Y. Immunolocalisation of heat shock protein 72 and glycoprotein 96 in colonic adenocarcinoma. Acta Histochem 2007; 110:117-23. [PMID: 18155754 DOI: 10.1016/j.acthis.2007.10.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2007] [Revised: 09/14/2007] [Accepted: 10/01/2007] [Indexed: 01/05/2023]
Abstract
Heat shock protein 72 (HSP72) and glycoprotein 96 (gp96) are highly expressed in cancer tissues. Recent studies indicate the possible roles of HSP72 and gp96 in the development and progression of colonic carcinomas, but detailed information is still ambiguous. In this study, we investigated the correlation between clinical pathology and immunolocalisation of HSP72 and gp96 in human colonic carcinoma. The distribution of HSP72 and gp96 was studied in 160 human colonic carcinomas, with or without metastasis, as well as in mucous membranes adjacent to cancers by means of immunohistochemistry. HSP72 immunoreactivity was detected in 145 of 160 primary tumours (90.6%) and in 44 of 160 mucous membranes adjacent to cancers (27.5%). Gp96 was detected in 81.3% colonic carcinomas and in 13.8% mucous membranes adjacent to cancer. Immunolocalisation of HSP72 and gp96 was mainly cytoplasmic. HSP72 and gp96 immunolabelling was significantly higher in colonic carcinomas with metastasis than in those without metastasis (P<0.05). The results indicate a significant correlation between the immunopositivity of HSP72 and gp96 and the progression of colonic carcinomas. Immunolabelling of HSP72 and gp96 may be useful as diagnostic or prognostic markers in colonic carcinoma.
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Che J, Doubrovin M, Serganova I, Ageyeva L, Beresten T, Finn R, Blasberg R. HSP70-Inducible hNIS-IRES-eGFP Reporter Imaging: Response to Heat Shock. Mol Imaging 2007. [DOI: 10.2310/7290.2007.00036] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Jiantu Che
- From the Departments of Neurology and Radiology, Memorial Hospital, Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Mikhail Doubrovin
- From the Departments of Neurology and Radiology, Memorial Hospital, Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Inna Serganova
- From the Departments of Neurology and Radiology, Memorial Hospital, Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Lyudmila Ageyeva
- From the Departments of Neurology and Radiology, Memorial Hospital, Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Tatiana Beresten
- From the Departments of Neurology and Radiology, Memorial Hospital, Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Ronald Finn
- From the Departments of Neurology and Radiology, Memorial Hospital, Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Ronald Blasberg
- From the Departments of Neurology and Radiology, Memorial Hospital, Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
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Sun Y, Bai Y, Song D, Li X, Wang L, Zhang H. Design and performances of immunoassay based on SPR biosensor with magnetic microbeads. Biosens Bioelectron 2007; 23:473-8. [PMID: 17764924 DOI: 10.1016/j.bios.2007.06.016] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2007] [Revised: 06/11/2007] [Accepted: 06/15/2007] [Indexed: 10/23/2022]
Abstract
A surface plasmon resonance (SPR) biosensor system was developed for immunoassay, based on the conjugates of magnetic microbeads coupling with antibody which could be trapped on the Au film firmly due to the magnetic force. The magnetic microbeads were used as the solid support for the heat shock protein 70 (Hsp 70) antibody and antibody immobilized magnetic microbeads were utilized instead of the single antibody for the determination of Hsp 70. Since the magnetic bead is coated with dextran, the antibodies and some specific biomolecular receptors can be immobilized using a variety of chemical reactions. Compared to traditional antibody immobilization on the sensing film, there is not a covalent link between the Au film and the antibody. There is a great advantage in that sensor can be stripped and reused, and the same chemistry used to derivative dextran-coated SPR sensors can be used for the magnetic bead-coated sensors. The sensing layer was formed well. Different dilution ratios (v/v) of the conjugates result in different detectable ranges. When the dilution ratios of the conjugate are 1:10 and 1:5, the lowest concentrations of Hsp 70 that can be detected are 1.50 and 0.30 microg ml(-1), respectively.
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Affiliation(s)
- Ying Sun
- College of Chemistry, Jilin University, Changchun 130012, PR China
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Chang XR, Peng L, Yi SX, Peng Y, Yan J. Association of high expression in rat gastric mucosal heat shock protein 70 induced by moxibustion pretreatment with protection against stress injury. World J Gastroenterol 2007; 13:4355-9. [PMID: 17708611 PMCID: PMC4250864 DOI: 10.3748/wjg.v13.i32.4355] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To study the effect of moxibustion on Zusanli or Liangmeng point on gastric mucosa injury in stress-induced ulcer rats and its correlation with the expression of heat shock protein 70 (HSP70).
METHODS: Sixty healthy SD rats (30 males, 30 females) were divided into control group, injury model group, Zushanli point group, Liangmeng point group. Stress gastric ulcer model was induced by binding cold stress method. Gastric mucosa ulcer injury (UI) index was calculated by Guth method. Gastric mucosa blood flow (GMBF) was recorded with a biological signal analyzer. Protein content and gene expression in gastric mucosal HSP70 were detected by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR). Thiobarbital method was used to determine malondialdehyde (MDA) content. Gastric mucosal endothelin (ET) and prostaglandin E2 (PGE2) were analyzed by radioimmunoassay.
RESULTS: High gastric mucosal UI index, high HSP70 expression, low GMBF and PGF2, elevated MDA and ET were observed in gastric mucosa of rats subjected to cold stress. Moxibustion on Zusanli or Liangmeng point decreased rat gastric mucosal UI index, MDA and ET. Conversely, the expression of HSP70, GMBF, and PGE2 was elevated in gastric mucosa after pretreatment with moxibustion on Zusanli or Liangmeng point. The observed parameters were significantly different between Zusanli and Liangmeng points.
CONCLUSION: Pretreatment with moxibustion on Zusanli or Liangmeng point protects gastric mucosa against stress injury. This protection is associated with the higher expression of HSP70 mRNA and protein, leading to release of PGE2 and inhibition of MDA and ET, impairment of gastric mucosal index.
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Affiliation(s)
- Xiao-Rong Chang
- College of Acupuncture and Massage, Hunan University of Traditional Chinese Medicine, , 113 Shaoshan Mid-Road, Changsha 410007, Hunan Province, China.
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Chiang SL, Jiang SS, Wang YJ, Chiang HC, Chen PH, Tu HP, Ho KY, Tsai YS, Chang IS, Ko YC. Characterization of Arecoline-Induced Effects on Cytotoxicity in Normal Human Gingival Fibroblasts by Global Gene Expression Profiling. Toxicol Sci 2007; 100:66-74. [PMID: 17682004 DOI: 10.1093/toxsci/kfm201] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Areca nut is the most widely used psychoactive substance and an important environmental risk factor for development of oral premalignant lesions and cancer. Arecoline, the major alkaloid of areca nut, has been known to cause cytotoxicity and genotoxicity in mammalian cells in vivo and in vitro and even contributes to carcinogenicity. However, the susceptible genes accounting for arecoline-induced damage in normal human oral cells are still lacking, which possibly involves in initial molecular damage via alternation of gene expression level on biological pathways. The present study was undertaken to characterize the toxic effects of arecoline in gene expression profiling on normal human gingival fibroblasts (HGF) using cDNA microarray and quantitative real-time reverse transcription PCR. The cytotoxicity of arecoline on HGF-1 cell line was elevated in a dose-dependent manner (p < 0.05) accompanied with distinct morphological change and formation of intracellular vacuoles were observed. At optimum concentration of arecoline determined from dose-response curve of the cytotoxicity, a large number of genes were significantly repressed than induced by arecoline in global gene expression profiling. Five induced- and seven repressed genes including glutathione synthetase were further validated, and their gene expression changes were increased in a dose-dependent manner in a concentration range of 50-150 microg/ml. In conclusion, we proposed a tentative model to explain arecoline-induced effects on contribution of oral pathogenesis. The findings identified that 12 susceptible genes can potentially serve as biomarkers of arecoline-induced damage in betel chewers.
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Affiliation(s)
- Shang-Lun Chiang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan, ROC
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Wang XP, Wang QX, Ying XP. Correlation between clinicopathology and expression of heat shock protein 72 and glycoprotein 96 in human gastric adenocarcinoma. TOHOKU J EXP MED 2007; 212:35-41. [PMID: 17464101 DOI: 10.1620/tjem.212.35] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Heat shock protein 72 (HSP72) and glycoprotein 96 (gp96) are highly expressed in cancer tissues. Recent studies indicate the possible roles of HSP72 and gp96 in the development and progression of gastric carcinomas but detailed information is still ambiguous. In this study, we investigated the correlation between clinicopathology and expression of HSP72 and gp96 in human gastric carcinoma. The expression of HSP72 and gp96 was studied in 60 human gastric carcinomas with or without metastasis as well as in mucous membrane adjacent to cancers by way of immunohistochemistry. HSP72 immunoreactivities were detected in 54 of 60 primary tumors (90.0%) and in 22 of 60 mucous membranes adjacent to cancers (36.7%). Likewise, gp96 immunoreactivities were detected in 49 cases of gastric carcinoma (81.7%) and in 15 samples of mucous membrane adjacent to cancer (25.0%). Both HSP72 and gp96 were stained in cytoplasm. HSP72 and gp96 expression in colonic carcinomas with metastasis was significantly higher than those with non-metastasis (p < 0.05). The results indicate that there exists a significant correlation between the expression of HSP72 and gp96 and the progression of gastric carcinomas. The high-level expression of HSP72 and gp96 may be used as diagnostic or prognostic markers for gastric carcinoma.
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Affiliation(s)
- Xiao-Ping Wang
- Department of Pathology, Shaanxi University of Chinese Medicine, Shaanxi, China.
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Yi SX, Peng Y, Chang XR, Peng N, Yan J, Lin YP. Effect of pre-moxibustion on apoptosis and proliferation of gastric mucosa cells. World J Gastroenterol 2007; 13:2174-8. [PMID: 17465496 PMCID: PMC4146839 DOI: 10.3748/wjg.v13.i15.2174] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the effects of pre-moxibustion on apoptosis and proliferation of gastric mucosal cell in rats with stress-induced ulcer, and to analyze the relationship between those effects and the expression of heat-shock protein 70 (HSP70).
METHODS: Sixty healthy Sprague Dawley rats were randomly assigned into four groups, namely group A, B, C and D. The animal model of stress ulcer was established by water immersion and restraint stress. The rats in group A, B, and D served as the restraint, model, and non-acupoint controls, respectively, while those in group C received moxibustion at Zusanli and Liangmen points. Immunohistochemical methodology was used to detect the expression of HSP70, apoptosis index (AI, × 10-6/μm2) and proliferation index (PCNA-LI, × 10-6/μm2). The mucosal expression of transforming growth factor α (TGF-α) was detected by radioimmunoassay.
RESULTS: Moxibustion at Zusanli and Liangmen points significantly decreased the gastric injury and the apoptosis of gastric mucosal cells, while markedly increased the mucosal expression of TGF-α and HSP70 as well as the proliferation of gastric mucosal cells. Compared with group A, ulcer index (UI) (26.8 ± 9.8 vs 12.0 ± 5.9, P < 0.01), AI (9.6 ± 4.2 vs 4.4 ± 2.6, P < 0.05) and expression of HSP70 (9.6 ± 4.2 vs 4.4 ± 2.6, P < 0.05) were significantly increased, but the content of TGF-α (104.7 ± 51.2 pg/mL vs 254.0 ± 86.9 pg/mL, P < 0.01) and PCNA-LI (6.9 ± 4.7 vs 14.9 ± 4.6, P < 0.05) were significantly decreased in group B. However, ulcer index values (UI) and AI were obviously lower in group C compared to groups B and D (14.1 ± 5.4 vs 26.8 ± 9.8 and 26.2 ± 7.7, P < 0.01; 3.0 ± 1.6 vs 9.6 ± 4.2 and 8.2 ± 5.2, P < 0.05, respectively), but content of TGF-α (237.0 ± 72.6 pg/mL vs 104.7 ± 51.2 pg/mL and 154.1 ± 61.3 pg/mL, P < 0.01) and expression of HSP70 (0.13 ± 0.03 vs 0.08 ± 0.06 and 0.06 ± 0.04, P < 0.05) were higher in group C. Furthermore, the PCNA-LI was significantly higher in group C than in group B (21.6 ± 4.1 vs 6.9 ± 4.7, P < 0.01).
CONCLUSION: Moxibustion at Zusanli and Liangmen points has a protective effect on rats gastric mucosa in stress-induced gastric ulcer, which is closely related to its actions in promoting synthesis of TGF-α and proliferation of gastric mucosal cells, suppressing gastric mucosal cell apoptosis, and up-regulating HSP70 expression.
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Affiliation(s)
- Shou-Xiang Yi
- Institute of Acupuncture and Massage, Hunan University of Traditional Chinese Medicine, 113 Shaoshan Middle Road, Changsha 410007, Hunan Province, China.
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Abstract
Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.
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Affiliation(s)
- Guido Kroemer
- Institut Gustave Roussy, Institut National de la Santé et de la Recherche Médicale Unit "Apoptosis, Cancer and Immunity," Université de Paris-Sud XI, Villejuif, France
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