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Updated: May 25, 2026
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Adseverin: a novel cisplatin-resistant marker in the human bladder cancer cell line HT1376 identified by quantitative
Noriyoshi Miura1, Nobuaki Takemori, Tadahiko Kikugawa
1Department of Urology, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Japan. norimiurajp@yahoo.co.jp
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.
Insights
Cisplatin resistance in bladder cancer involves increased adseverin (SCIN) in mitochondria, which interacts with voltage-dependent anion channels (VDACs). Targeting this VDAC-SCIN interaction may overcome chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cisplatin is a primary bladder cancer treatment, but resistance develops, hindering therapy.
- Understanding chemoresistance mechanisms is crucial for improving bladder cancer treatment outcomes.
Purpose of the Study:
- To investigate the molecular mechanisms of cisplatin resistance in human bladder cancer cells.
- To identify novel therapeutic targets for overcoming cisplatin resistance.
Main Methods:
- Established a cisplatin-resistant bladder cancer cell line (HT1376-CisR).
- Utilized comparative proteomics (2D gel electrophoresis and mass spectrometry) to analyze protein expression differences.
- Performed mRNA knockdown, immunoprecipitation, and apoptosis assays.
Main Results:
- Identified 36 differentially expressed proteins between cisplatin-sensitive and resistant cells.
- Found significant overexpression of adseverin (SCIN) in resistant cells, particularly in mitochondria.
- Demonstrated that SCIN knockdown restores mitochondria-mediated apoptosis and that SCIN binds to VDACs in mitochondria.
Conclusions:
- The VDAC-SCIN interaction in mitochondria may inhibit apoptosis in cisplatin-resistant bladder cancer cells.
- Targeting the VDAC-SCIN interaction presents a potential new therapeutic strategy for cisplatin-resistant bladder cancer.
