Abstract 3770: MLN4924, a neddylation inhibitor, abolishes chemoresistance of bladder cancer stem-like cells through suppression of stemness

Abstract

Abstract Introduction: Bladder urothelial carcinoma (UC) ranks fourth in incidence among cancers in men and eighth in women in the United States, however, the chemotherapy response rate is only about half. The cancer stem cells (CSCs), which are believed as the driving force of tumor progression, have related to chemoresistance. Here we present the finding of CSC-like cells from human UC cell line NTUB1, and investigate the effect of MLN4924, a neddylation inhibitor on conquering chemoresistance in human UC. Materials & methods: The CSC-like cells were enriched from its parental cell line NTUB1 by cisplatin selection consecutively for at least one year. The properties of CSC-like cells were demonstrated by colony formation assay, side population assay, and cell viability assay. The expression levels of specific stemness-related markers, EMT-related markers and cell death-related molecules were revealed by western blot. The ability of migration was analyzed by wound-healing assay and transwell assay. The MLN4924-induced apoptosis on CSC-like cells were determined by flow cytometry with annexin V and propidium iodide (PI) staining. Gene knockdown was performed with gene-specific siRNA. The in vitro findings were further confirmed in vivo via xenograft mouse model. Results: The CSC-like cells exhibited multiple drug resistance, highly expression level of stemness markers as well as EMT markers, and highly mobility. The treatment of MLN4924 repressed the expression of stemness markers and EMT markers and reduced cell mobility; meanwhile, it caused significant cell death in CSC-like cells. The knockdown of stemness markers diminished the drug resistance of CSC-like cells. And in the end, MLN4924 significantly inhibit tumor growth in xenograft models bladder cancer stem-like cells. Conclusion: Our data suggested that the drug resistance in UC may conferred by CSC-like cells via up-regulation of stemness markers, and the treatment of MLN4924 could abolish drug resistance through repression of stemness markers. This could provide a new remedy for bladder cancer treatment. Citation Format: Kuan-Lin Kuo, I-Lin Ho, Yeong-Shiau Pu, Yu-Chieh Tsai, Tsung-Hsien Shih, Kuo-How Huang. MLN4924, a neddylation inhibitor, abolishes chemoresistance of bladder cancer stem-like cells through suppression of stemness. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3770. doi:10.1158/1538-7445.AM2014-3770