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

doi:10.1038/srep16948

MLN4924 Synergistically Enhances Cisplatin-induced Cytotoxicity via JNK and Bcl-xL Pathways in Human Urothelial Carcinoma

Sci Rep. 2015 Nov 23:5:16948. doi: 10.1038/srep16948.

Authors

Affiliations

¹ Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
² Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Graduate Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁴ Department of Pathology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
⁵ Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Apoptosis / genetics
Carcinoma, Transitional Cell / drug therapy*
Carcinoma, Transitional Cell / genetics
Carcinoma, Transitional Cell / metabolism
Carcinoma, Transitional Cell / pathology
Caspase 3 / genetics
Caspase 3 / metabolism
Caspase 7 / genetics
Caspase 7 / metabolism
Cell Line, Tumor
Cisplatin / pharmacology*
Cyclopentanes / pharmacology*
Drug Combinations
Drug Synergism
Gene Expression Regulation, Neoplastic
Histones / genetics
Histones / metabolism
Humans
MAP Kinase Kinase 4 / genetics*
MAP Kinase Kinase 4 / metabolism
Mice
Mice, Nude
NEDD8 Protein
Neoplasm Grading
Poly(ADP-ribose) Polymerases / genetics
Poly(ADP-ribose) Polymerases / metabolism
Pyrimidines / pharmacology*
Signal Transduction
Ubiquitins / genetics
Ubiquitins / metabolism
Urinary Bladder Neoplasms / drug therapy*
Urinary Bladder Neoplasms / genetics
Urinary Bladder Neoplasms / metabolism
Urinary Bladder Neoplasms / pathology
Xenograft Model Antitumor Assays
bcl-X Protein / antagonists & inhibitors
bcl-X Protein / genetics*
bcl-X Protein / metabolism

Substances

Antineoplastic Agents
BCL2L1 protein, human
Cyclopentanes
Drug Combinations
H2AX protein, human
Histones
NEDD8 Protein
NEDD8 protein, human
Pyrimidines
Ubiquitins
bcl-X Protein
Poly(ADP-ribose) Polymerases
MAP Kinase Kinase 4
CASP3 protein, human
CASP7 protein, human
Caspase 3
Caspase 7
Cisplatin
pevonedistat