Adseverin: A novel cisplatin-resistant marker in the human bladder cancer cell line HT1376 identified by quantitative proteomic analysis

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• 作者：Noriyoshi Miura^a ; ^{norimiurajp@yahoo.co.jp} ; ^{nmiura@m.ehime-u.ac.jp} ; Nobuaki Takemori^b ; Tadahiko Kikugawa^a ; Nozomu Tanji^a ; Shigeki Higashiyama^c ; ^d ; Masayoshi Yokoyama^a
• 关键词：Urothelial carcinoma ; Cisplatin ; Drug resistant ; Adseverin ; Proteomics
• 刊名：Molecular Oncology
• 出版年：2012
• 期刊代码：226_15747891
• 类别：med
• 出版时间：June, 2012
• 卷：6
• 期：3
• 页码：311-322
• 文件大小：1113 K

摘要

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 expressed 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.