期刊
MOLECULAR ONCOLOGY
卷 6, 期 3, 页码 311-322出版社
WILEY
DOI: 10.1016/j.molonc.2011.12.002
关键词
Urothelial carcinoma; Cisplatin; Drug resistant; Adseverin; Proteomics
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan (Program for Enhancing Systematic Education in Graduate School)
- Grants-in-Aid for Scientific Research [23701084] Funding Source: KAKEN
Cisplatin is currently the most effective antitumor agent available against bladder cancer. However, a majority of patients eventually relapse with cisplatin-resistant disease. Chemoresistance thus remains a major obstacle in bladder cancer therapy. To clarify the molecular mechanisms underlying cisplatin resistance in bladder cancer, we established a cisplatin-resistant subline from the human bladder cancer cell line HT1376 (HT1376-CisR), and conducted large-scale analyses of the incpressed proteins using two-dimensional (2D) gel electrophoresis coupled with mass spectrometry (MS). Comparative proteomic analysis of HT1376 and HT1376-CisR cells revealed 36 differentially expressed proteins, wherein 21 proteins were upregulated and 15 were downregulated in HT1376-CisR cells. Among the differentially regulated proteins, adseverin (SCIN), a calcium-dependent actin-binding protein, was overexpressed (4-fold upregulation) in HT1376-CisR, with the increase being more prominent in the mitochondrial fraction than in the cytosol fraction. SCIN mRNA knockdown significantly reduced cell proliferation with mitochondria-mediated apoptosis in HT1376-cisR cells. Immunoprecipitation analysis revealed voltage-dependent anion channels (VDACs) to be bound to SCIN in the mitochondrial fraction. Our results suggest that the VDAC-SCIN interaction may inhibit mitochondria-mediated apoptosis in cisplatin-resistant cells. Targeting the vDAC-SCIN interaction may offer a new therapeutic strategy for cisplatin-resistant bladder cancer. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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