MLN4924 synergistically enhances cisplatin-induced cytotoxicity via jnk and bcl-xl pathways in human urothelial carcinoma

I. Lin Ho, Kuan Lin Kuo, Shing Hwa Liu, Hong Chiang Chang, Ju Ton Hsieh, June Tai Wu, Chih Kang Chiang, Wei Chou Lin, Yu Chieh Tsai, Chien Tso Chou, Chen Hsun Hsu, Yeong Shiau Pu, Chung Sheng Shi, Kuo How Huang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

38 Scopus citations

Abstract

Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma. However, the response rate is only 40-65%. This study investigated the anti-tumor effect and underlying mechanisms of the combination of cisplatin and the NEDD8-activating enzyme inhibitor MLN4924 in human bladder urothelial carcinoma. The combination of cisplatin and MLN4924 exerted synergistic cytotoxicity on two high-grade bladder urothelial carcinoma cell lines, NTUB1 and T24 (combination index <1). MLN4924 also potentiated the cisplatin-induced apoptosis and activation of caspase-3 and -7, phospho-histone H2A.X and PARP. c-Jun N-terminal kinase (JNK) activation and a down-regulation of B-cell lymphoma-extra large (Bcl-xL) were also observed during cisplatin and MLN4924 treatment. Inhibition of JNK activation partially restored cell viability and Bcl-xL expression. Bcl-xL overexpression also rescued cell viability. MLN4924 significantly potentiated cisplatin-induced tumor suppression in urothelial carcinoma xenograft mice. In summary, MLN4924 synergistically enhanced the anti-tumor effect of cisplatin via an increase in DNA damage, JNK activation and down-regulation of Bcl-xL in urothelial carcinoma cells. These findings provide a new therapeutic strategy for the treatment of bladder cancer.

Original languageEnglish
Article number16948
JournalScientific Reports
Volume5
DOIs
StatePublished - 23 11 2015

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