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Cheng CY, Chen YL, Ho H, Huang CY, Chu SE, Liang YJ. Prognostic Significance of DNAJB4 Expression in Gastric Cancer: Correlation with CD31, Caspase-3, and Tumor Progression. Diagnostics (Basel) 2025; 15:652. [PMID: 40149995 PMCID: PMC11941126 DOI: 10.3390/diagnostics15060652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 02/28/2025] [Accepted: 03/03/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Gastric cancer is one of the most common and lethal cancers worldwide, with particularly high incidence and mortality rates in East Asia and Europe. DNAJB4 has been shown to have prognostic implications in other cancer types; however, its expression patterns and role in gastric cancer have not been extensively studied. This study aimed to analyze DNAJB4 expression in gastric cancer and explore its association with clinical characteristics, molecular markers, and patient outcomes. Methods: We selected suitable tumor samples from 189 gastric cancer patients who had not undergone chemotherapy or radiotherapy, with 188 patients ultimately included in the analysis. Tissue microarray and immunohistochemistry were used to evaluate DNAJB4 expression, and the samples were divided into high- and low-expression groups based on the H-score. Multivariate logistic regression and survival analysis were conducted to identify influencing factors. Results: High DNAJB4 expression was significantly correlated with increased CD31 levels but was inversely associated with advanced cancer stages. Subgroup analysis revealed that in patients with advanced gastric cancer, high DNAJB4 expression was associated with increased caspase-3 levels and with elevated CD31 and decreased E-cadherin levels. Conclusions: High DNAJB4 expression was associated with both angiogenesis and apoptosis, indicating its complex role in gastric cancer progression. Although DNAJB4 promoted angiogenesis by increasing CD31 levels, it may also enhance apoptosis in tumor cells through caspase-3-induced apoptosis.
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Affiliation(s)
- Chiao-Yin Cheng
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Yen-Lin Chen
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114201, Taiwan;
| | - Hua Ho
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Chun-Yen Huang
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Sheng-En Chu
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
- Department of Emergency Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliu City 640203, Taiwan
| | - Yao-Jen Liang
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department and Institute of Life Science, Fu-Jen Catholic University, New Taipei 242062, Taiwan
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Luo WJ, Hsu WL, Lu CY, Chien MH, Chang JH, Su KY. DNAJB4/HLJ1 deficiency sensitizes diethylnitrosamine-induced hepatocarcinogenesis with peritumoral STAT3 activation. Cell Biol Toxicol 2024; 41:20. [PMID: 39738726 PMCID: PMC11685265 DOI: 10.1007/s10565-024-09978-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 12/21/2024] [Indexed: 01/02/2025]
Abstract
Environmental chemicals and toxins are known to impact human health and contribute to cancer developments. Among these, genotoxins induce genetic mutations critical for cancer initiation. In the liver, proliferation serves not only as a compensatory mechanism for tissue repair but also as a potential risk factor for the progression of premalignant lesions. The role of Human Liver DnaJ-Like Protein (DNAJB4/HLJ1), a stress-responsive heat shock protein 40, in genotoxin-induced liver carcinogenesis remains unexplored. Using whole-genome transcriptomic analysis, we demonstrate that HLJ1 deficiency in mice results in altered gene signatures enriched in pathways associated with chemically induced liver cancer and IL-6/STAT3 signaling activation. Employing diethylnitrosamine (DEN) as a carcinogen, we further reveal that STAT3 and H2AX phosphorylation induced by short-term DEN treatment are amplified in HLJ1-deficient mice. In long-term DEN experiments, HLJ1 deletion enhances tumor proliferation and progression, accompanied by pronounced STAT3 phosphorylation in normal tissues rather than in tumor regions. The tumor-suppressive role of peritumoral HLJ1 is validated through the transplantation of HLJ1-wildtype B16F1 and LLC cancer cell lines into syngeneic HLJ1-deficient mice, which exhibits an augmented tumorigenic phenotype compared to wildtype controls. This study uncovers a previously unrecognized role of HLJ1 in suppressing liver carcinogenesis via the downregulation of STAT3 signaling in peritumoral normal cells. These findings suggest that HLJ1 reinforcement represents a promising strategy for liver cancer treatment and prevention.
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Affiliation(s)
- Wei-Jia Luo
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wei-Lun Hsu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chih-Yun Lu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Min-Hui Chien
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jung-Hsuan Chang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kang-Yi Su
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan.
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Jin X, Zhang Y, Hu W, Liu C, Cai D, Sun J, Wei Q, Cai Q. Developing a prognostic model for hepatocellular carcinoma based on MED19 and clinical stage and determining MED19 as a therapeutic target. J Cancer Res Clin Oncol 2024; 150:446. [PMID: 39369139 PMCID: PMC11455706 DOI: 10.1007/s00432-024-05978-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 09/27/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUD Mediator complex subunit 19 (MED19), a member of the mediator complex, has been demonstrated to involve in tumorigenesis of hepatocellular carcinoma (HCC). However, the regulation mechanisms of MED19, the immune landscape linking MED19 to HCC and its predictive value of immunotherapy treatment in HCC are so far unknown. METHODS Here, we analyzed data from The Cancer Genome Atlas and other databases to assess the expression of MED19 and its prognosis and therapeutical-targets impact in HCC. RESULTS MED19 expression was upregulated in HCC tissues compared to non-tumorous liver tissues and that its upregulation was positively associated with advanced clinicopathology features. The multivariate analysis showed that MED19 was an independent predictor of outcome in HCC. In vitro experiments revealed that MED19 knockdown suppressed hepG2 cells proliferation, colony forming and invasion and induced apoptosis. Furthermore, MED19 inhibition resulted in G0/G1 phase arrest in hepG2 cells. We screened differentially expressed genes between low and high MED19 expression groups. Enrichment analyses showed that these genes were mainly linked to nuclear division and cell cycle. The pattern of tumor-infiltrating immune was demonstrated to be related with MED19 expression in HCC. TIDE analyses showed that patients in the low-expression group presented significantly better immunotherapy. Moreover, we developed a predicted model for HCC patient's prognosis. Receiver operating characteristic analyses revealed that this model processed a favorable performance in predicting the prognosis of HCC patients. Finally, a nomogram was built for predicting survival probability of individual HCC patient. CONCLUSION These findings suggest that MED19 as a novel biomarker that has significant association with immune landscape and immunotherapy response in HCC. The proposed prediction model composed of MED19 and pathological stage has a better role in determining prognosis and stratifying of HCC.
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Affiliation(s)
- Xiaojun Jin
- The Affiliated Lihuili Hospital of Ningbo University, Health Science Center, Ningbo University, 57 Xingning Rd., Ningbo, Zhejiang, China
| | - Yun Zhang
- Department of Ophthalmology, The Third Affiliated Hospital of Southern Medical University, SouthernMedical University, Guangzhou, China
| | - Wei Hu
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chang Liu
- Department of Hepatological Surgery, Bethune Third Clinical Medical College, Jilin University, Changchun, China
| | - Danyang Cai
- Department of Radiation Oncology, Taizhou Hospital, Taizhou, Zhejiang, China
| | - Jialin Sun
- School of Statistics, East China Normal University, Shanghai, China
| | - Qichun Wei
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qun Cai
- The Affiliated Lihuili Hospital of Ningbo University, Health Science Center, Ningbo University, 57 Xingning Rd., Ningbo, Zhejiang, China.
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Kunachowicz D, Król-Kulikowska M, Raczycka W, Sleziak J, Błażejewska M, Kulbacka J. Heat Shock Proteins, a Double-Edged Sword: Significance in Cancer Progression, Chemotherapy Resistance and Novel Therapeutic Perspectives. Cancers (Basel) 2024; 16:1500. [PMID: 38672583 PMCID: PMC11048091 DOI: 10.3390/cancers16081500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Heat shock proteins (Hsps) are involved in one of the adaptive mechanisms protecting cells against environmental and metabolic stress. Moreover, the large role of these proteins in the carcinogenesis process, as well as in chemoresistance, was noticed. This review aims to draw attention to the possibilities of using Hsps in developing new cancer therapy methods, as well as to indicate directions for future research on this topic. In order to discuss this matter, a thorough review of the latest scientific literature was carried out, taking into account the importance of selected proteins from the Hsp family, including Hsp27, Hsp40, Hsp60, Hsp70, Hsp90 and Hsp110. One of the more characteristic features of all Hsps is that they play a multifaceted role in cancer progression, which makes them an obvious target for modern anticancer therapy. Some researchers emphasize the importance of directly inhibiting the action of these proteins. In turn, others point to their possible use in the design of cancer vaccines, which would work by inducing an immune response in various types of cancer. Due to these possibilities, it is believed that the use of Hsps may contribute to the progress of oncoimmunology, and thus help in the development of modern anticancer therapies, which would be characterized by higher effectiveness and lower toxicity to the patients.
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Affiliation(s)
- Dominika Kunachowicz
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (D.K.); (M.K.-K.)
| | - Magdalena Król-Kulikowska
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (D.K.); (M.K.-K.)
| | - Wiktoria Raczycka
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (W.R.); (J.S.); (M.B.)
| | - Jakub Sleziak
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (W.R.); (J.S.); (M.B.)
| | - Marta Błażejewska
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (W.R.); (J.S.); (M.B.)
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine Santariškių g. 5, LT-08406 Vilnius, Lithuania
- DIVE IN AI, 53-307 Wroclaw, Poland
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Zhou J, Li H, Wu B, Zhu L, Huang Q, Guo Z, He Q, Wang L, Peng X, Guo T. Network pharmacology combined with experimental verification to explore the potential mechanism of naringenin in the treatment of cervical cancer. Sci Rep 2024; 14:1860. [PMID: 38253629 PMCID: PMC10803340 DOI: 10.1038/s41598-024-52413-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 01/18/2024] [Indexed: 01/24/2024] Open
Abstract
Cervical cancer is the second leading cause of morbidity and mortality in women worldwide. Traditional treatment methods have become limited. Naringenin, a flavonoid abundant in various fruits and herbal medicines, has demonstrated anti-tumor properties among other effects. This research undertook to elucidate the mechanism of naringenin in the context of cervical cancer treatment by leveraging network pharmacology and performing experimental validation. Initial steps involved predicting potential naringenin targets and subsequently screening for overlaps between these targets and those related to cervical cancer, followed by analysis of their interrelationships. Molecular docking was subsequently utilized to verify the binding effect of the central target. Within the framework of network pharmacology, it was discovered that naringenin might possess anti-cancer properties specific to cervical cancer. Following this, the anti-tumor effects of naringenin on Hela cell viability, migration, and invasion were assessed employing CCK-8, transwell, wound healing assays, and western blotting. Experimental data indicated that naringenin attenuates the migration and invasion of Hela cells via downregulation EGFR/PI3K/AKT signaling pathway. Thus, our findings suggest that naringenin has therapeutic impacts on cervical cancer via multiple mechanisms, primarily by inhibiting the migration and invasion through the EGFR/PI3K/AKT/mTOR pathway. This study offers fresh insights for future clinical studies.
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Affiliation(s)
- Ji Zhou
- Medical School, Changsha Social Work College, Changsha, China
- The First Affiliated Hospital of Changsha Medical University, Changsha, China
| | - Haoying Li
- The First Affiliated Hospital of Changsha Medical University, Changsha, China
| | - Ben Wu
- The First Affiliated Hospital of Changsha Medical University, Changsha, China
- Wuzhou Medical college, Wuzhou, China
| | - Lemei Zhu
- The First Affiliated Hospital of Changsha Medical University, Changsha, China
| | - Qiao Huang
- The First Affiliated Hospital of Changsha Medical University, Changsha, China
| | - Zhenyu Guo
- The First Affiliated Hospital of Changsha Medical University, Changsha, China
| | - Qizhi He
- The First Affiliated Hospital of Changsha Medical University, Changsha, China
| | - Lin Wang
- The First Affiliated Hospital of Changsha Medical University, Changsha, China.
| | - Xiaozhen Peng
- School of Public Health & Laboratory Medicine, Hunan University of Medicine, Huaihua, China.
| | - Tianyao Guo
- Department of Pathology, The Second Xiangya Hospital of Central South University, Changsha, China.
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, The Second Xiangya Hospital of Central South University, Changsha, China.
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Asgharzadeh F, Moradi-Marjaneh R, Marjaneh MM. The role of heat shock protein 40 in carcinogenesis and biology of colorectal cancer. Curr Pharm Des 2022; 28:1457-1465. [PMID: 35570564 DOI: 10.2174/1381612828666220513124603] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 03/31/2022] [Indexed: 11/22/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. Despite the enormous amount of effort in the diagnosis and treatment of CRC, the overall survival rate of patients remains low. The precise molecular and cellular basis underlying CRC has not been completely understood yet. Over time, new genes and molecular pathways involved in the pathogenesis of the disease are being identified. Accurate discovery of these genes and signaling pathways are important and urgent missions for the next generation of anticancer therapy research. Chaperone DnaJ, also known as Hsp40 (heat shock protein 40), has been of particular interest in CRC pathogenesis, as it is involved in the fundamental cell activities for maintaining cellular homeostasis. Evidence show that protein family members of DnaJ/Hsp40 play both roles; enhancing and reducing the growth of CRC cells. In the present review, we focus on the current knowledge on the molecular mechanisms responsible for the role of DnaJ/Hsp40 in CRC carcinogenesis and biology.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reyhaneh Moradi-Marjaneh
- Department of Physiology, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Mahdi Moradi Marjaneh
- Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, United Kingdom
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Damiani V, Cufaro MC, Fucito M, Dufrusine B, Rossi C, Del Boccio P, Federici L, Turco MC, Sallese M, Pieragostino D, De Laurenzi V. Proteomics Approach Highlights Early Changes in Human Fibroblasts-Pancreatic Ductal Adenocarcinoma Cells Crosstalk. Cells 2022; 11:1160. [PMID: 35406724 PMCID: PMC8997741 DOI: 10.3390/cells11071160] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 03/23/2022] [Accepted: 03/26/2022] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality worldwide. Non-specific symptoms, lack of biomarkers in the early stages, and drug resistance due to the presence of a dense fibrous stroma all contribute to the poor outcome of this disease. The extracellular matrix secreted by activated fibroblasts contributes to the desmoplastic tumor microenvironment formation. Given the importance of fibroblast activation in PDAC pathology, it is critical to recognize the mechanisms involved in the transformation of normal fibroblasts in the early stages of tumorigenesis. To this aim, we first identified the proteins released from the pancreatic cancer cell line MIA-PaCa2 by proteomic analysis of their conditioned medium (CM). Second, normal fibroblasts were treated with MIA-PaCa2 CM for 24 h and 48 h and their proteostatic changes were detected by proteomics. Pathway analysis indicated that treated fibroblasts undergo changes compatible with the activation of migration, vasculogenesis, cellular homeostasis and metabolism of amino acids and reduced apoptosis. These biological activities are possibly regulated by ITGB3 and TGFB1/2 followed by SMAD3, STAT3 and BAG3 activation. In conclusion, this study sheds light on the crosstalk between PDAC cells and associated fibroblasts. Data are available via ProteomeXchange with identifier PXD030974.
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Affiliation(s)
- Verena Damiani
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (V.D.); (M.F.); (B.D.); (C.R.); (L.F.); (M.S.); (V.D.L.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (M.C.C.); (P.D.B.)
| | - Maria Concetta Cufaro
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (M.C.C.); (P.D.B.)
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Maurine Fucito
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (V.D.); (M.F.); (B.D.); (C.R.); (L.F.); (M.S.); (V.D.L.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (M.C.C.); (P.D.B.)
| | - Beatrice Dufrusine
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (V.D.); (M.F.); (B.D.); (C.R.); (L.F.); (M.S.); (V.D.L.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (M.C.C.); (P.D.B.)
| | - Claudia Rossi
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (V.D.); (M.F.); (B.D.); (C.R.); (L.F.); (M.S.); (V.D.L.)
- Department of Psychological, Health and Territory Sciences, School of Medicine and Health Sciences, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Piero Del Boccio
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (M.C.C.); (P.D.B.)
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Luca Federici
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (V.D.); (M.F.); (B.D.); (C.R.); (L.F.); (M.S.); (V.D.L.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (M.C.C.); (P.D.B.)
| | - Maria Caterina Turco
- Department of Medicine, Surgery and Dentistry Schola Medica Salernitana, University of Salerno, 84081 Baronissi, Italy;
- R&D Division, BIOUNIVERSA s.r.l., 84081 Baronissi, Italy
| | - Michele Sallese
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (V.D.); (M.F.); (B.D.); (C.R.); (L.F.); (M.S.); (V.D.L.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (M.C.C.); (P.D.B.)
| | - Damiana Pieragostino
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (V.D.); (M.F.); (B.D.); (C.R.); (L.F.); (M.S.); (V.D.L.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (M.C.C.); (P.D.B.)
| | - Vincenzo De Laurenzi
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (V.D.); (M.F.); (B.D.); (C.R.); (L.F.); (M.S.); (V.D.L.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (M.C.C.); (P.D.B.)
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Cyran AM, Zhitkovich A. Heat Shock Proteins and HSF1 in Cancer. Front Oncol 2022; 12:860320. [PMID: 35311075 PMCID: PMC8924369 DOI: 10.3389/fonc.2022.860320] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 02/07/2022] [Indexed: 12/23/2022] Open
Abstract
Fitness of cells is dependent on protein homeostasis which is maintained by cooperative activities of protein chaperones and proteolytic machinery. Upon encountering protein-damaging conditions, cells activate the heat-shock response (HSR) which involves HSF1-mediated transcriptional upregulation of a group of chaperones - the heat shock proteins (HSPs). Cancer cells experience high levels of proteotoxic stress due to the production of mutated proteins, aneuploidy-induced excess of components of multiprotein complexes, increased translation rates, and dysregulated metabolism. To cope with this chronic state of proteotoxic stress, cancers almost invariably upregulate major components of HSR, including HSF1 and individual HSPs. Some oncogenic programs show dependence or coupling with a particular HSR factor (such as frequent coamplification of HSF1 and MYC genes). Elevated levels of HSPs and HSF1 are typically associated with drug resistance and poor clinical outcomes in various malignancies. The non-oncogene dependence ("addiction") on protein quality controls represents a pancancer target in treating human malignancies, offering a potential to enhance efficacy of standard and targeted chemotherapy and immune checkpoint inhibitors. In cancers with specific dependencies, HSR components can serve as alternative targets to poorly druggable oncogenic drivers.
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Affiliation(s)
- Anna M Cyran
- Legoretta Cancer Center, Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, United States
| | - Anatoly Zhitkovich
- Legoretta Cancer Center, Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, United States
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9
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Zhang B, Fan Y, Cao P, Tan K. Multifaceted roles of HSF1 in cell death: A state-of-the-art review. Biochim Biophys Acta Rev Cancer 2021; 1876:188591. [PMID: 34273469 DOI: 10.1016/j.bbcan.2021.188591] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/24/2021] [Accepted: 07/11/2021] [Indexed: 02/08/2023]
Abstract
Cell death is a common and active process that is involved in various biological processes, including organ development, morphogenesis, maintaining tissue homeostasis and eliminating potentially harmful cells. Abnormal regulation of cell death significantly contributes to tumor development, progression and chemoresistance. The mechanisms of cell death are complex and involve not only apoptosis and necrosis but also their cross-talk with other types of cell death, such as autophagy and the newly identified ferroptosis. Cancer cells are chronically exposed to various stresses, such as lack of oxygen and nutrients, immune responses, dysregulated metabolism and genomic instability, all of which lead to activation of heat shock factor 1 (HSF1). In response to heat shock, oxidative stress and proteotoxic stresses, HSF1 upregulates transcription of heat shock proteins (HSPs), which act as molecular chaperones to protect normal cells from stresses and various diseases. Accumulating evidence suggests that HSF1 regulates multiple types of cell death through different signaling pathways as well as expression of distinct target genes in cancer cells. Here, we review the current understanding of the potential roles and molecular mechanism of HSF1 in regulating apoptosis, autophagy and ferroptosis. Deciphering HSF1-regulated signaling pathways and target genes may help in the development of new targeted anti-cancer therapeutic strategies.
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Affiliation(s)
- Bingwei Zhang
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China; Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Yumei Fan
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China
| | - Pengxiu Cao
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China
| | - Ke Tan
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
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Zhang Z, Jing J, Ye Y, Chen Z, Jing Y, Li S, Hong W, Ruan H, Liu Y, Hu Q, Wang J, Li W, Lin C, Diao L, Zhou Y, Han L. Characterization of the dual functional effects of heat shock proteins (HSPs) in cancer hallmarks to aid development of HSP inhibitors. Genome Med 2020; 12:101. [PMID: 33225964 PMCID: PMC7682077 DOI: 10.1186/s13073-020-00795-6] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 10/30/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Heat shock proteins (HSPs), a representative family of chaperone genes, play crucial roles in malignant progression and are pursued as attractive anti-cancer therapeutic targets. Despite tremendous efforts to develop anti-cancer drugs based on HSPs, no HSP inhibitors have thus far reached the milestone of FDA approval. There remains an unmet need to further understand the functional roles of HSPs in cancer. METHODS We constructed the network for HSPs across ~ 10,000 tumor samples from The Cancer Genome Atlas (TCGA) and ~ 10,000 normal samples from Genotype-Tissue Expression (GTEx), and compared the network disruption between tumor and normal samples. We then examined the associations between HSPs and cancer hallmarks and validated these associations from multiple independent high-throughput functional screens, including Project Achilles and DRIVE. Finally, we experimentally characterized the dual function effects of HSPs in tumor proliferation and metastasis. RESULTS We comprehensively analyzed the HSP expression landscape across multiple human cancers and revealed a global disruption of the co-expression network for HSPs. Through analyzing HSP expression alteration and its association with tumor proliferation and metastasis, we revealed dual functional effects of HSPs, in that they can simultaneously influence proliferation and metastasis in opposite directions. We experimentally characterized the dual function of two genes, DNAJC9 and HSPA14, in lung cancer cells. We further demonstrated the generalization of this dual direction of associations between HSPs and cancer hallmarks, suggesting the necessity to more carefully evaluate HSPs as therapeutic targets and develop highly specific HSP inhibitors for cancer intervention. CONCLUSIONS Our study furnishes a holistic view of functional associations of HSPs with cancer hallmarks to aid the development of HSP inhibitors as well as other drugs in cancer therapy.
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Affiliation(s)
- Zhao Zhang
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Ji Jing
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA
| | - Youqiong Ye
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Zhiao Chen
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Ying Jing
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Shengli Li
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Wei Hong
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Hang Ruan
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Yaoming Liu
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Qingsong Hu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jun Wang
- Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Wenbo Li
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Chunru Lin
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Lixia Diao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Yubin Zhou
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA.
| | - Leng Han
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
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11
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Lavin KM, Ge Y, Sealfon SC, Nair VD, Wilk K, McAdam JS, Windham ST, Kumar PL, McDonald MLN, Bamman MM. Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson's Disease. Front Physiol 2020; 11:653. [PMID: 32625117 PMCID: PMC7311784 DOI: 10.3389/fphys.2020.00653] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 05/22/2020] [Indexed: 12/18/2022] Open
Abstract
Parkinson's disease (PD) is the most common motor neurodegenerative disease, and neuromuscular function deficits associated with PD contribute to disability. Targeting these symptoms, our laboratory has previously evaluated 16-week high-intensity resistance exercise as rehabilitative training (RT) in individuals with PD. We reported significant improvements in muscle mass, neuromuscular function (strength, power, and motor unit activation), indices of neuromuscular junction integrity, total and motor scores on the unified Parkinson's disease rating scale (UPDRS), and total and sub-scores on the 39-item PD Quality of Life Questionnaire (PDQ-39), supporting the use of RT to reverse symptoms. Our objective was to identify transcriptional networks that may contribute to RT-induced neuromuscular remodeling in PD. We generated transcriptome-wide skeletal muscle RNA-sequencing in 5 participants with PD [4M/1F, 67 ± 2 years, Hoehn and Yahr stages 2 (n = 3) and 3 (n = 2)] before and after 16-week high intensity RT to identify transcriptional networks that may in part underpin RT-induced neuromuscular remodeling in PD. Following RT, 304 genes were significantly upregulated, notably related to remodeling and nervous system/muscle development. Additionally, 402 genes, primarily negative regulators of muscle adaptation, were downregulated. We applied the recently developed Pathway-Level Information ExtractoR (PLIER) method to reveal coordinated gene programs (as latent variables, LVs) that differed in skeletal muscle among young (YA) and old (OA) healthy adults and PD (n = 12 per cohort) at baseline and in PD pre- vs. post-RT. Notably, one LV associated with angiogenesis, axon guidance, and muscle remodeling was significantly lower in PD than YA at baseline and was significantly increased by exercise. A different LV annotated to denervation, autophagy, and apoptosis was increased in both PD and OA relative to YA and was also reduced by 16-week RT in PD. Thus, this analysis identified two novel skeletal muscle transcriptional programs that are dysregulated by PD and aging, respectively. Notably, RT has a normalizing effect on both programs in individuals with PD. These results identify potential molecular transducers of the RT-induced improvements in neuromuscular remodeling and motor function that may aid in optimizing exercise rehabilitation strategies for individuals with PD.
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Affiliation(s)
- Kaleen M. Lavin
- Department of Cell, Developmental and Integrative Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- UAB Center for Exercise Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Yongchao Ge
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Stuart C. Sealfon
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Venugopalan D. Nair
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Katarzyna Wilk
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jeremy S. McAdam
- Department of Cell, Developmental and Integrative Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- UAB Center for Exercise Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Samuel T. Windham
- UAB Center for Exercise Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Preeti Lakshman Kumar
- Department of Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Merry-Lynn N. McDonald
- Department of Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Marcas M. Bamman
- Department of Cell, Developmental and Integrative Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- UAB Center for Exercise Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Birmingham/Atlanta VA Geriatric Research, Education, and Clinical Center, Birmingham, AL, United States
- Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
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12
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Role of Mycoplasma Chaperone DnaK in Cellular Transformation. Int J Mol Sci 2020; 21:ijms21041311. [PMID: 32075244 PMCID: PMC7072988 DOI: 10.3390/ijms21041311] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/04/2020] [Accepted: 02/12/2020] [Indexed: 12/25/2022] Open
Abstract
Studies of the human microbiome have elucidated an array of complex interactions between prokaryotes and their hosts. However, precise bacterial pathogen-cancer relationships remain largely elusive, although several bacteria, particularly those establishing persistent intra-cellular infections, like mycoplasmas, can alter host cell cycles, affect apoptotic pathways, and stimulate the production of inflammatory substances linked to DNA damage, thus potentially promoting abnormal cell growth and transformation. Consistent with this idea, in vivo experiments in several chemically induced or genetically deficient mouse models showed that germ-free conditions reduce colonic tumor formation. We demonstrate that mycoplasma DnaK, a chaperone protein belonging to the Heath shock protein (Hsp)-70 family, binds Poly-(ADP-ribose) Polymerase (PARP)-1, a protein that plays a critical role in the pathways involved in recognition of DNA damage and repair, and reduces its catalytic activity. It also binds USP10, a key p53 regulator, reducing p53 stability and anti-cancer functions. Finally, we showed that bystander, uninfected cells take up exogenous DnaK-suggesting a possible paracrine function in promoting cellular transformation, over and above direct mycoplasma infection. We propose that mycoplasmas, and perhaps certain other bacteria with closely related DnaK, may have oncogenic activity, mediated through the inhibition of DNA repair and p53 functions, and may be involved in the initiation of some cancers but not necessarily involved nor necessarily even be present in later stages.
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13
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Doxycycline inhibits electric field-induced migration of non-small cell lung cancer (NSCLC) cells. Sci Rep 2019; 9:8094. [PMID: 31147570 PMCID: PMC6542854 DOI: 10.1038/s41598-019-44505-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 05/15/2019] [Indexed: 01/01/2023] Open
Abstract
Adenocarcinoma, large cell carcinoma and squamous cell carcinoma are the most commonly diagnosed subtypes of non-small cell lung cancers (NSCLC). Numerous lung cancer cell types have exhibited electrotaxis under direct current electric fields (dcEF). Physiological electric fields (EF) play key roles in cancer cell migration. In this study, we investigated electrotaxis of NSCLC cells, including human large cell lung carcinoma NCI-H460 and human lung squamous cell carcinoma NCI-H520 cells. Non-cancerous MRC-5 lung fibroblasts were included as a control. After dcEF stimulation, NCI-H460 and NCI-H520 cells, which both exhibit epithelial-like morphology, migrated towards the cathode, while MRC-5 cells, which have fibroblast-like morphology, migrated towards the anode. The effect of doxycycline, a common antibiotic, on electrotaxis of MRC-5, NCI-H460 and NCI-H520 cells was examined. Doxycycline enhanced the tested cells’ motility but inhibited electrotaxis in the NSCLC cells without inhibiting non-cancerous MRC-5 cells. Based on our finding, further in-vivo studies could be devised to investigate the metastasis inhibition effect of doxycycline in an organism level.
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14
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Acun T, Doberstein N, Habermann JK, Gemoll T, Thorns C, Oztas E, Ried T. HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2018; 21:257-265. [PMID: 28481734 DOI: 10.1089/omi.2017.0016] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Breast cancer is the most common cancer type and cause of cancer-related mortality among women worldwide. New biomarker discovery is crucial for diagnostic innovation and personalized medicine in breast cancer. Heat shock proteins (HSPs) have been increasingly reported as biomarkers and potential drug targets for cancers. HLJ1 (DNAJB4) belongs to the DNAJ (HSP40) family of HSPs and is regarded as a tumor suppressor gene in lung, colon, and gastric cancers. However, the role of the HLJ1 gene in breast cancer is currently unknown. We evaluated the role of the HLJ1 gene in breast cancer progression by analyzing its in vitro and in vivo expression and its genetic/epigenetic alterations. HLJ1 expression was found to be reduced or lost in breast cancer cell lines (SK-BR-3, MDA-MB-231, ZR-75-1) compared with the nontumorigenic mammary epithelial cell line (MCF 10A). In a clinical context for breast cancer progression, the HLJ1 expression was significantly less frequent in invasive breast carcinoma samples (n = 230) compared with normal breast tissue (n = 100), benign neoplasia (n = 53), and ductal carcinoma in situ (n = 21). In methylation analyses by the combined bisulfite restriction analysis assay, the CpG island located in the 5'-flanking region of the HLJ1 gene was found to be methylated in breast cancer cell lines. HLJ1 expression was restored in the ZR-75-1 cell line by DNA demethylating agent 5-Aza-2'-deoxycytidine (5-AzadC) and histone deacetylase inhibitor trichostatin A. These new observations support the idea that HLJ1 is a tumor suppressor candidate and potential biomarker for breast cancer. Epigenomic mechanisms such as CpG methylation and histone deacetylation might contribute to downregulation of HLJ1 expression. We call for future functional, epigenomic, and clinical studies to ascertain the contribution of HLJ1 to breast cancer pathogenesis and, importantly, evaluate its potential for biomarker development in support of personalized medicine diagnostic innovation in clinical oncology.
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Affiliation(s)
- Tolga Acun
- 1 Department of Molecular Biology and Genetics, Bülent Ecevit University , Zonguldak, Turkey
| | - Natalie Doberstein
- 2 Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein , Lübeck, Germany
| | - Jens K Habermann
- 2 Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein , Lübeck, Germany
| | - Timo Gemoll
- 2 Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein , Lübeck, Germany
| | - Christoph Thorns
- 3 Institute of Pathology, University of Lübeck and University Medical Center Schleswig-Holstein , Lübeck, Germany
| | - Emin Oztas
- 4 Department of Medical Histology and Embryology, Gülhane Military Medical Academy , Ankara, Turkey
| | - Thomas Ried
- 5 Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland
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15
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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: 477] [Impact Index Per Article: 53.0] [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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16
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Şimşek E, Aydemir EA, İmir N, Koçak O, Kuruoğlu A, Fışkın K. Dimethyl sulfoxide-caused changes in pro- and anti-angiogenic factor levels could contribute to an anti-angiogenic response in HeLa cells. Neuropeptides 2015; 53:37-43. [PMID: 26275957 DOI: 10.1016/j.npep.2015.07.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 07/14/2015] [Accepted: 07/16/2015] [Indexed: 12/31/2022]
Abstract
Dimethyl sulfoxide (DMSO) is widely used in biological research as a general solvent. While it has been previously demonstrated that DMSO possesses a wide range of pharmacological effects, there is no published work regarding the effects of DMSO on pro-angiogenic factor levels. This study was designed to investigate the possible effects of DMSO on the levels of three pro-angiogenic factors released from HeLa cells in vitro. Cells were treated with two different and previously determined concentrations of DMSO. The cytotoxic effects of DMSO concentrations on HeLa cells were determined via MTT. Survival rates of DMSO-treated cells were determined by Invitrogen live/dead viability/cytotoxicity kit and trypan blue exclusion assay. Changes in the pro-angiogenic levels in media were evaluated by Cayman's Substance P Enzyme Immunoassay ELISA kit. Vascular endothelial growth factor ELISA kit and interferon gamma ELISA kit for substance P, VEGF and IFNγ respectively. Changes in substance P levels were corrected by standard western blotting. Changes in VEGF and IFNγ levels were corrected both by western blot and real time PCR. Treatment with 1.4 μM DMSO caused a time-dependent inhibition of cell proliferation at 24, 48 and 72 h. 1.4 μM DMSO caused a significant reduction in VEGF levels at 72 h of incubation and sharp increases in IFNγ levels at both 48 and 72 h of incubation. According to real time PCR analyses, DMSO (1.4 μM) exhibited an inhibitory effect on VEGF but acted as an augmenter of IFNγ release on HeLa cells in vitro. This is the first report showing that the general solvent DMSO suppressed HeLa cell proliferation, decreased the levels of two pro-angiogenic factors (substance P and VEGF) and increased the release of an anti-angiogenic factor IFNγ in vitro.
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Affiliation(s)
- Ece Şimşek
- Department of Nutrition and Dietetics, Antalya School of Health, Akdeniz University, 07058 Antalya, Turkey.
| | - Esra Arslan Aydemir
- Department of Biology, Faculty of Arts and Sciences, Akdeniz University, 07058 Antalya, Turkey.
| | - Nilüfer İmir
- Department of Biology Education, Faculty of Education, Institute of Life Sciences, Akdeniz University, 07058 Antalya, Turkey.
| | - Orhan Koçak
- Department of Biology, Faculty of Arts and Sciences, Akdeniz University, 07058 Antalya, Turkey.
| | - Aykut Kuruoğlu
- Department of Biology, Faculty of Arts and Sciences, Akdeniz University, 07058 Antalya, Turkey.
| | - Kayahan Fışkın
- Department of Biology, Faculty of Arts and Sciences, Akdeniz University, 07058 Antalya, Turkey.
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17
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Yuan A, Hsiao YJ, Chen HY, Chen HW, Ho CC, Chen YY, Liu YC, Hong TH, Yu SL, Chen JJW, Yang PC. Opposite Effects of M1 and M2 Macrophage Subtypes on Lung Cancer Progression. Sci Rep 2015; 5:14273. [PMID: 26399191 PMCID: PMC4585843 DOI: 10.1038/srep14273] [Citation(s) in RCA: 256] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 08/24/2015] [Indexed: 12/11/2022] Open
Abstract
Macrophages in a tumor microenvironment have been characterized as M1- and M2-polarized subtypes. Here, we discovered the different macrophages' impacts on lung cancer cell A549. The M2a/M2c subtypes promoted A549 invasion and xenograft tumor growth. The M1 subtype suppressed angiogenesis. M1 enhanced the sensitivity of A549 to cisplatin and decreased the tube formation activity and cell viability of A549 cells by inducing apoptosis and senescence. Different macrophage subtypes regulated genes involved in the immune response, cytoskeletal remodeling, coagulation, cell adhesion, and apoptosis pathways in A549 cells, which was a pattern that correlated with the altered behaviors of the A549 cells. Furthermore, we found that the identified M1/M2 gene signatures were significantly correlated with the extended overall survival of lung cancer patients. These results suggest that M1/M2 gene expression signature may be used as a prognostic indicator for lung cancer patients, and M1/M2 polarization may be a target of investigation of immune-modulating therapies for lung cancer in the future.
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Affiliation(s)
- Ang Yuan
- Departments of Chest Medicine and Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Jing Hsiao
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsuan-Yu Chen
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Huei-Wen Chen
- Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chao-Chi Ho
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Yun Chen
- Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Chia Liu
- Departments of Chest Medicine and Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tsai-Hsia Hong
- Departments of Surgery, National Taiwan University Hospital, Taipei, Taiwan.,General Education Center, National Defense University, Taipei, Taiwan
| | - Sung-Liang Yu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan.,Center for Optoelectronic Biomedicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jeremy J W Chen
- Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan.,Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan
| | - Pan-Chyr Yang
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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18
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Lin SY, Chang HH, Lai YH, Lin CH, Chen MH, Chang GC, Tsai MF, Chen JJW. Digoxin Suppresses Tumor Malignancy through Inhibiting Multiple Src-Related Signaling Pathways in Non-Small Cell Lung Cancer. PLoS One 2015; 10:e0123305. [PMID: 25955608 PMCID: PMC4425490 DOI: 10.1371/journal.pone.0123305] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 03/03/2015] [Indexed: 11/19/2022] Open
Abstract
Non-small cell lung cancer is the predominant type of lung cancer, resulting in high mortality worldwide. Digoxin, a cardiac glycoside, has recently been suggested to be a novel chemotherapeutic agent. Src is an oncogene that plays an important role in cancer progression and is therefore a potential target for cancer therapy. Here, we investigated whether digoxin could suppress lung cancer progression through the inhibition of Src activity. The effects of digoxin on lung cancer cell functions were investigated using colony formation, migration and invasion assays. Western blotting and qPCR assays were used to analyze the mRNA and protein expression levels of Src and its downstream proteins, and a cell viability assay was used to measure cellular cytotoxicity effects. The results of the cell function assays revealed that digoxin inhibited the proliferation, invasion, migration, and colony formation of A549 lung cancer cells. Similar effects of digoxin were also observed in other lung cancer cell lines. Furthermore, we found that digoxin significantly suppressed Src activity and its protein expression in a dose- and time-dependent manner as well as reduced EGFR and STAT3 activity. Our data suggest that digoxin is a potential anticancer agent that may suppress lung cancer progression through inhibiting Src and the activity of related proteins.
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Affiliation(s)
- Sheng-Yi Lin
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - Hsiu-Hui Chang
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Hua Lai
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ching-Hsiung Lin
- Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Min-Hsuan Chen
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Gee-Chen Chang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Meng-Feng Tsai
- Department of Molecular Biotechnology, Dayeh University, Changhua, Taiwan
- * E-mail: (MFT); (JJWC)
| | - Jeremy J. W. Chen
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
- * E-mail: (MFT); (JJWC)
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19
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Tsai MF, Wang CC, Chen JJW. Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in non-small cell lung cancer. World J Clin Oncol 2014; 5:865-873. [PMID: 25493224 PMCID: PMC4259948 DOI: 10.5306/wjco.v5.i5.865] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/10/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality throughout the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancers. Despite considerable progress in the diagnosis and treatment of the disease, the overall 5-year survival rate of NSCLC patients remains lower than 15%. The most common causes of death in lung cancer patients are treatment failure and metastasis. Therefore, developing novel strategies that target both tumour growth and metastasis is an important and urgent mission for the next generation of anticancer therapy research. Heat shock proteins (HSPs), which are involved in the fundamental defence mechanism for maintaining cellular viability, are markedly activated during environmental or pathogenic stress. HSPs facilitate rapid cell division, metastasis, and the evasion of apoptosis in cancer development. These proteins are essential players in the development of cancer and are prime therapeutic targets. In this review, we focus on the current understanding of the molecular mechanisms responsible for HLJ1’s role in lung cancer carcinogenesis and progression. HLJ1, a member of the human HSP 40 family, has been characterised as a tumour suppressor. Research studies have also reported that HLJ1 shows promising dual anticancer effects, inhibiting both tumour growth and metastasis in NSCLC. The accumulated evidence suggests that HLJ1 is a potential biomarker and treatment target for NSCLC.
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Yu Q, Li Q, Lu P, Chen Q. Polyphyllin D induces apoptosis in U87 human glioma cells through the c-Jun NH2-terminal kinase pathway. J Med Food 2014; 17:1036-42. [PMID: 25045920 DOI: 10.1089/jmf.2013.2957] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Polyphyllin D (PD), an active component from a traditional medicinal herb Paris polyphylla, which has long been used for the treatment of cancer in Asian countries, has been found to hold significant antitumor activity in vivo or in vitro. However, there were few reports on the effects and underlying mechanism of PD on apoptosis in U87 human glioma cells. The present study was conducted to evaluate apoptotic induction of PD in U87 human glioma cells, and explore its underlying pathway. U87 glioma cells were cultured and treated with varied concentrations of PD (from 10(-8) to 10(-4) M). The inhibition of U87 glioma cell proliferation by PD was assessed by MTT assay. The apoptosis of U87 glioma cells was detected by flow cytometry, and western blot analysis was used to examine human B-cell leukemia/lymphoma 2 (Bcl-2), human Bcl-2 associated X protein (Bax), caspase-3, total-c-jun NH2-terminal kinase (t-JNK), and phosphorylation-JNK (p-JNK) protein expression in U87 human glioma cells. The treatment with PD for 24 h significantly inhibited the proliferation of U87 human glioma cells in a concentration-dependent manner. PD increased apoptosis and significantly upregulated the expression of Bax, caspase-3, and p-JNK associated with apoptosis, but downregulated antiapoptotic Bcl-2 expression in U87 human glioma cells. Our data provided evidences that PD induces apoptosis in U87 human glioma cells. This effect might be associated with the JNK pathway.
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Affiliation(s)
- Qiang Yu
- 1 Department of Neurosurgery, Renmin Hospital of Wuhan University , Wuhan, China
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21
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Wong YH, Chen RH, Chen BS. Core and specific network markers of carcinogenesis from multiple cancer samples. J Theor Biol 2014; 362:17-34. [PMID: 25016045 DOI: 10.1016/j.jtbi.2014.05.045] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 05/19/2014] [Accepted: 05/28/2014] [Indexed: 01/07/2023]
Abstract
Cancer is the leading cause of death worldwide and is generally caused by mutations in multiple proteins or the dysregulation of pathways. Understanding the causes and the underlying carcinogenic mechanisms can help fight this disease. In this study, a systems biology approach was used to construct the protein-protein interaction (PPI) networks of four cancers and the non-cancers by their corresponding microarray data, PPI modeling and database-mining. By comparing PPI networks between cancer and non-cancer samples to find significant proteins with large PPI changes during carcinogenesis process, core and specific network markers were identified by the intersection and difference of significant proteins, respectively, with carcinogenesis relevance values (CRVs) for each cancer. A total of 28 significant proteins were identified as core network markers in the carcinogenesis of four types of cancer, two of which are novel cancer-related proteins (e.g., UBC and PSMA3). Moreover, seven crucial common pathways were found among these cancers based on their core network markers, and some specific pathways were particularly prominent based on the specific network markers of different cancers (e.g., the RIG-I-like receptor pathway in bladder cancer, the proteasome pathway and TCR pathway in liver cancer, and the HR pathway in lung cancer). Additional validation of these network markers using the literature and new tested datasets could strengthen our findings and confirm the proposed method. From these core and specific network markers, we could not only gain an insight into crucial common and specific pathways in the carcinogenesis, but also obtain a high promising PPI target for cancer therapy.
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Affiliation(s)
- Yung-Hao Wong
- Lab of Control and Systems Biology, Department of Electrical Engineering National Tsing Hua University, Hsinchu 30013, Taiwan.
| | - Ru-Hong Chen
- Lab of Control and Systems Biology, Department of Electrical Engineering National Tsing Hua University, Hsinchu 30013, Taiwan.
| | - Bor-Sen Chen
- Lab of Control and Systems Biology, Department of Electrical Engineering National Tsing Hua University, Hsinchu 30013, Taiwan.
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Liu Y, Zhou J, Zhang C, Fu W, Xiao X, Ruan S, Zhang Y, Luo X, Tang M. HLJ1 is a novel biomarker for colorectal carcinoma progression and overall patient survival. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:969-977. [PMID: 24696714 PMCID: PMC3971299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 02/12/2014] [Indexed: 06/03/2023]
Abstract
The implication of HLJ1, a member of the heat shock protein-40 chaperone family, in colorectal carcinoma (CRC) remains unclear. The aim of this study was to determine the dynamic changes of HLJ1 in CRC both in vitro and in vivo, and the relationship between its level and the survival rate of CRC patients. Both real-time RT-PCR and Western blot were used to detect the expression of HLJ1 in CRC cells, while the distribution of HLJ1 in CRC and its adjacent normal mucosa tissues from CRC patients was determined with immunohistochemistry. Moreover, MTT and in vitro invasive assays were performed to determine the effect of HLJ1 overexpression on cell proliferation and invasion of CRC cells. The results indicated that in highly metastatic CRC cells, the HLJ1 expression was lower than that in lowly metastatic ones, and that the overexpression of HLJ1 significantly inhibited CRC cell proliferation and invasion in vitro. Interestingly, the HLJ1 expression was significantly down-regulated in CRC or lymphatic metastatic tissues from patient, compared to that in the normal mucosa (P<0.05), and the HLJ1 expression was correlated strongly with lymph metastasis, Dukes' stage, and remote metastasis (P<0.05). Most surprisingly, patients with a higher HLJ1 level had a better overall survival rate, compared to that in patients with lower HLJ1 level (P<0.05). Based on all these findings, we conclude that HLJ1 is a strong tumor suppressor for CRC, and thus the down-regulation of the HLJ1 expression may be used as a biomarker to predict clinical outcome of patients with CRC.
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Affiliation(s)
- Yong Liu
- Department of Pathology, The Affiliated Hospital of Luzhou Medical CollegeZhongshan Road 319, Luzhou, 646000, China
| | - Jie Zhou
- Department of Neurosurgery, The Affiliated Hospital of Luzhou Medical CollegeTaiping Road 25, Luzhou, 646000, China
| | - Cuiwei Zhang
- Department of Pathology, The Affiliated Hospital of Luzhou Medical CollegeZhongshan Road 319, Luzhou, 646000, China
| | - Wenguang Fu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Luzhou Medical CollegeTaiping Road 25, Luzhou, 646000, China
| | - Xiuli Xiao
- Department of Pathology, The Affiliated Hospital of Luzhou Medical CollegeZhongshan Road 319, Luzhou, 646000, China
| | - Sibei Ruan
- Department of Pathology, The Affiliated Hospital of Luzhou Medical CollegeZhongshan Road 319, Luzhou, 646000, China
| | - Yuan Zhang
- Department of Pathology, The Affiliated Hospital of Luzhou Medical CollegeZhongshan Road 319, Luzhou, 646000, China
| | - Xia Luo
- Department of Pathology, The Affiliated Hospital of Luzhou Medical CollegeZhongshan Road 319, Luzhou, 646000, China
| | - Mingxi Tang
- Department of Pathology, The Affiliated Hospital of Luzhou Medical CollegeZhongshan Road 319, Luzhou, 646000, China
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Wang CC, Lin SY, Lai YH, Liu YJ, Hsu YL, Chen JJW. Dimethyl sulfoxide promotes the multiple functions of the tumor suppressor HLJ1 through activator protein-1 activation in NSCLC cells. PLoS One 2012; 7:e33772. [PMID: 22529897 PMCID: PMC3328470 DOI: 10.1371/journal.pone.0033772] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Accepted: 02/21/2012] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Dimethyl sulfoxide (DMSO) is an amphipathic molecule that displays a diversity of antitumor activities. Previous studies have demonstrated that DMSO can modulate AP-1 activity and lead to cell cycle arrest at the G1 phase. HLJ1 is a newly identified tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. Its transcriptional activity is regulated by the transcription factor AP-1. However, the effects of DMSO on HLJ1 are still unknown. In the present study, we investigate the antitumor effects of DMSO through HLJ1 induction and demonstrate the mechanisms involved. METHODS AND FINDINGS Low-HLJ1-expressing highly invasive CL1-5 lung adenocarcinoma cells were treated with various concentrations of DMSO. We found that DMSO can significantly inhibit cancer cell invasion, migration, proliferation, and colony formation capabilities through upregulation of HLJ1 in a concentration-dependent manner, whereas ethanol has no effect. In addition, the HLJ1 promoter and enhancer reporter assay revealed that DMSO transcriptionally upregulates HLJ1 expression through an AP-1 site within the HLJ1 enhancer. The AP-1 subfamily members JunD and JunB were significantly upregulated by DMSO in a concentration-dependent manner. Furthermore, pretreatment with DMSO led to a significant increase in the percentage of UV-induced apoptotic cells. CONCLUSIONS Our results suggest that DMSO may be an important stimulator of the tumor suppressor protein HLJ1 through AP-1 activation in highly invasive lung adenocarcinoma cells. Targeted induction of HLJ1 represents a promising approach for cancer therapy, which also implied that DMSO may serve as a potential lead compound or coordinated ligand for the development of novel anticancer drugs.
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Affiliation(s)
- Chi-Chung Wang
- Graduate Institute of Basic Medicine, Fu Jen Catholic University, Taipei, Taiwan
- * E-mail: (JJWC); (CCW)
| | - Sheng-Yi Lin
- Institutes of Biomedical Sciences and Molecular Biology, National Chung-Hsing University, Taichung, Taiwan
| | - Yi-Hua Lai
- Institutes of Biomedical Sciences and Molecular Biology, National Chung-Hsing University, Taichung, Taiwan
| | - Ya-Jung Liu
- Graduate Institute of Basic Medicine, Fu Jen Catholic University, Taipei, Taiwan
| | - Yuan-Lin Hsu
- Graduate Institute of Basic Medicine, Fu Jen Catholic University, Taipei, Taiwan
| | - Jeremy J. W. Chen
- Institutes of Biomedical Sciences and Molecular Biology, National Chung-Hsing University, Taichung, Taiwan
- * E-mail: (JJWC); (CCW)
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Prostate apoptosis response 4 (Par-4), a novel substrate of caspase-3 during apoptosis activation. Mol Cell Biol 2011; 32:826-39. [PMID: 22184067 DOI: 10.1128/mcb.06321-11] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Prostate apoptosis response 4 (Par-4) is a ubiquitously expressed proapoptotic tumor suppressor protein. Here, we show for the first time, that Par-4 is a novel substrate of caspase-3 during apoptosis. We found that Par-4 is cleaved during cisplatin-induced apoptosis in human normal and cancer cell lines. Par-4 cleavage generates a C-terminal fragment of ~25 kDa, and the cleavage of Par-4 is completely inhibited by a caspase-3 inhibitor, suggesting that caspase-3 is directly involved in the cleavage of Par-4. Caspase-3-deficient MCF-7 cells do not show Par-4 cleavage in response to cisplatin treatment, and restoration of caspase-3 in MCF-7 cells produces a decrease in Par-4 levels, with the appearance of a cleaved fragment. Additionally, knockdown of Par-4 reduces caspase-3 activation and apoptosis induction. Site-directed mutagenesis reveals that Par-4 cleavage by caspase-3 occurs at an unconventional site, EEPD(131)↓G. Interestingly, overexpression of wild-type Par-4 but not the Par-4 D131A mutant sensitizes cells to cisplatin-induced apoptosis. Upon caspase-3 cleavage, the cleaved fragment of Par-4 accumulates in the nucleus and displays increased apoptotic activity. Overexpression of the cleaved fragment of Par-4 inhibits IκBα phosphorylation and blocks NF-κB nuclear translocation. We have identified a novel specific caspase-3 cleavage site in Par-4, and the cleaved fragment of Par-4 retains proapoptotic activity.
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25
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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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Lei JX, Cassone CG, Luebbert C, Liu QY. A novel neuron-enriched protein SDIM1 is down regulated in Alzheimer's brains and attenuates cell death induced by DNAJB4 over-expression in neuro-progenitor cells. Mol Neurodegener 2011; 6:9. [PMID: 21255413 PMCID: PMC3031242 DOI: 10.1186/1750-1326-6-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Accepted: 01/21/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Molecular changes in multiple biological processes contribute to the development of chronic neurodegeneration such as late onset Alzheimer's disease (LOAD). To discover how these changes are reflected at the level of gene expression, we used a subtractive transcription-based amplification of mRNA procedure to identify novel genes that have altered expression levels in the brains of Alzheimer's disease (AD) patients. Among the genes altered in expression level in AD brains was a transcript encoding a novel protein, SDIM1, that contains 146 amino acids, including a typical signal peptide and two transmembrane domains. Here we examined its biochemical properties and putative roles in neuroprotection/neurodegeneration. RESULTS QRT-PCR analysis of additional AD and control post-mortem human brains showed that the SDIM1 transcript was indeed significantly down regulated in all AD brains. SDIM1 is more abundant in NT2 neurons than astrocytes and present throughout the cytoplasm and neural processes, but not in the nuclei. In NT2 neurons, it is highly responsive to stress conditions mimicking insults that may cause neurodegeneration in AD brains. For example, SDIM1 was significantly down regulated 2 h after oxygen-glucose deprivation (OGD), though had recovered 16 h later, and also appeared significantly up regulated compared to untreated NT2 neurons. Overexpression of SDIM1 in neuro-progenitor cells improved cells' ability to survive after injurious insults and its downregulation accelerated cell death induced by OGD. Yeast two-hybrid screening and co-immunoprecipitation approaches revealed, both in vitro and in vivo, an interaction between SDIM1 and DNAJB4, a heat shock protein hsp40 homolog, recently known as an enhancer of apoptosis that also interacts with the mu opioid receptor in human brain. Overexpression of DNAJB4 alone significantly reduced cell viability and SDIM1 co-overexpression was capable of attenuating the cell death caused DNAJB4, suggesting that the binding of SDIM1 to DNAJB4 might sequester DNAJB4, thus increasing cell viability. CONCLUSION Taken together, we have identified a small membrane protein, which is down regulated in AD brains and neuronal cells exposed to injurious insults. Its ability to promote survival and its interaction with DNAJB4 suggest that it may play a very specific role in brain cell survival and/or receptor trafficking.
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Affiliation(s)
- Joy X Lei
- Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada.
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