title: MLN4924, a Novel NEDD8-activating enzyme inhibitor, exhibits antitumor activity and enhances cisplatin-induced cytotoxicity in human cervical carcinoma: in vitro and in vivo study.
abstract: MLN4924, an inhibitor of NEDD8 activating enzyme (NAE), has been reported to have activity against various malignancies. Here, we investigated the antitumor properties of MLN4924 and MLN4924 in combination with cisplatin on human cervical carcinoma (CC) in vitro and in vivo. Two human CC cell lines, ME-180 and HeLa, were used in this study. The cytotoxic effects of MLN4924 and/or cisplatin were measured by cell viability (MTT), proliferation (BrdU incorporation), apoptosis (flow cytometry with annexin V-FITC labeling), and the expression of cell apoptosis-related proteins (Western blotting). In vivo efficacy was determined in Nu/Nu nude mice with ME-180 and HeLa xenografts. The results showed that MLN4924 elicited viability inhibition, anti-proliferation and apoptosis in human CC cells, accompanied by activations of apoptosis-related molecules and Bid, Bcl-2 phosphorylation interruption, and interference with cell cycle regulators. Moreover, MLN4924 caused an endoplasmic reticulum stress response (caspase-4, ATF-4 and CHOP activations) and expression of other cellular stress molecules (JNK and c-Jun activations). Additionally, MLN4924 suppressed growth of CC xenografts in nude mice. Furthermore, we demonstrated that MLN4924 potentiated cisplatin-induced cytotoxicity in CC cells with activation of caspases. Consistently with this, MLN4924 significantly enhanced cisplatin-induced growth inhibition of CC xenografts. Together, these findings suggest that MLN4924 alone or in combination with cisplatin is of value in treating human CCs.
authors.affiliation: Graduate Institute of Pathology, National Taiwan University College of MedicineTaipei, Taiwan; Department of Pathology, National Taiwan University College of Medicine and HospitalTaipei, Taiwan.
authors.forename: Wei-Chou
authors.initials: WC
authors.lastname: Lin
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and HospitalTaipei, Taiwan; Graduate Institute of Toxicology, National Taiwan University College of MedicineTaipei, Taiwan.
authors.forename: Kuan-Lin
authors.initials: KL
authors.lastname: Kuo
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: Graduate Institute of Molecular Medicine, National Taiwan University College of Medicine Taipei, Taiwan.
authors.forename: June-Tai
authors.initials: JT
authors.lastname: Wu
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and Hospital Taipei, Taiwan.
authors.forename: Ju-Ton
authors.initials: JT
authors.lastname: Hsieh
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and Hospital Taipei, Taiwan.
authors.forename: Hong-Chiang
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and Hospital Taipei, Taiwan.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Liao
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and Hospital Taipei, Taiwan.
authors.forename: Chien-Tso
authors.initials: CT
authors.lastname: Chou
authors.affiliation: Graduate Institute of Toxicology, National Taiwan University College of Medicine Taipei, Taiwan.
authors.forename: Chih-Kang
authors.initials: CK
authors.lastname: Chiang
authors.affiliation: Graduate Institute of Oral Biology, National Yang-Ming University School of Dentistry Taipei, Taiwan.
authors.forename: Wei-Shuo
authors.initials: WS
authors.lastname: Chiu
authors.affiliation: Graduate Institute of Molecular Medicine, National Taiwan University College of Medicine Taipei, Taiwan.
authors.forename: Tzu-Yuan
authors.initials: TY
authors.lastname: Chiu
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and Hospital Taipei, Taiwan.
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and Hospital Taipei, Taiwan.
authors.forename: I-Lin
authors.initials: IL
authors.lastname: Ho
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and Hospital Taipei, Taiwan.
authors.forename: Zuo-He
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and Hospital Taipei, Taiwan.
authors.forename: Shih-Chen
authors.initials: SC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Toxicology, National Taiwan University College of Medicine Taipei, Taiwan.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Graduate Institute of Pathology, National Taiwan University College of MedicineTaipei, Taiwan; Department of Pathology, National Taiwan University College of Medicine and HospitalTaipei, Taiwan.
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.affiliation: Department of Urology, National Taiwan University College of Medicine and Hospital Taipei, Taiwan.
authors.forename: Kuo-How
authors.initials: KH
authors.lastname: Huang
keywords: MLN4924; apoptosis; cervical carcinoma; neddylation