title: MLN4924 Synergistically Enhances Cisplatin-induced Cytotoxicity via JNK and Bcl-xL Pathways in Human Urothelial Carcinoma.
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.
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: I-Lin
authors.initials: IL
authors.lastname: Ho
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kuan-Lin
authors.initials: KL
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shing-Hwa-
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hong-Chiang
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ju-Ton
authors.initials: JT
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: June-Tai
authors.initials: JT
authors.lastname: Wu
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Kang
authors.initials: CK
authors.lastname: Chiang
authors.affiliation: Department of Pathology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wei-Chou
authors.initials: WC
authors.lastname: Lin
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chien-Tso
authors.initials: CT
authors.lastname: Chou
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chen-Hsun
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chung-Sheng
authors.initials: CS
authors.lastname: Shi
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Kuo-How
authors.initials: KH
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003517:Cyclopentanes / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D000075687:NEDD8 Protein; D060787:Neoplasm Grading; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D003517:Cyclopentanes; D004338:Drug Combinations; C468783:H2AX protein, human; D006657:Histones; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D014452:Ubiquitins; D051020:bcl-X Protein; D011065:Poly(ADP-ribose) Polymerases; D048670:MAP Kinase Kinase 4; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D002945:Cisplatin; C539933:pevonedistat