title: Adseverin: a novel cisplatin-resistant marker in the human bladder cancer cell line HT1376 identified by quantitative proteomic analysis.
abstract: 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.
authors.affiliation: Department of Urology, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Japan. norimiurajp@yahoo.co.jp
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Miura
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Takemori
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Kikugawa
authors.forename: Nozomu
authors.initials: N
authors.lastname: Tanji
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015180:Electrophoresis, Gel, Two-Dimensional; D018260:Gelsolin / Q000494:pharmacology*; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D040901:Proteomics / Q000379:methods*; D021241:Spectrometry, Mass, Electrospray Ionization; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D014571:Urologic Neoplasms / Q000378:metabolism*
chemical_list: D018260:Gelsolin; C065395:scinderin; D002945:Cisplatin