title: The Nedd8-activating enzyme inhibitor MLN4924 induces autophagy and apoptosis to suppress liver cancer cell growth.
abstract: Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy.
authors.affiliation: Department of Immunology, Shanghai Medical College, and Biotherapy Research Center, Department of Digestive Diseases, Huashan Hospital, Shanghai, China.
authors.forename: Zhongguang
authors.initials: Z
authors.lastname: Luo
authors.forename: Guangyang
authors.initials: G
authors.lastname: Yu
authors.forename: Hyuk Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Lihui
authors.initials: L
authors.lastname: Li
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.forename: Dongqin
authors.initials: D
authors.lastname: Yang
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Pan
authors.forename: Chan
authors.initials: C
authors.lastname: Ding
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.forename: Jing
authors.initials: J
authors.lastname: Yi
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001483:Base Sequence; D003517:Cyclopentanes / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D000075687:NEDD8 Protein; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D014452:Ubiquitins / Q000037:antagonists & inhibitors*
chemical_list: D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D034741:RNA, Small Interfering; D014452:Ubiquitins; C539933:pevonedistat