title: Targeting Cullin-RING ligases by MLN4924 induces autophagy via modulating the HIF1-REDD1-TSC1-mTORC1-DEPTOR axis.
abstract: MLN4924, a newly discovered small molecule inhibitor of NEDD8-activating enzyme (NAE), inactivates Cullin-RING E3 ubiquitin Ligases (CRLs) by blocking cullin neddylation. As a result, MLN4924 causes accumulation of several key substrates of CRLs and effectively suppresses tumor cell growth by inducing apoptosis and senescence. However, the role of MLN4924 in induction of autophagy and its biological significance are totally unknown. Here we showed that MLN4924 effectively induces autophagy in both time- and dose-dependent manners in multiple human cancer lines, indicating a general phenomenon. Mechanistically, by inactivating CRLs, MLN4924 causes accumulation of DEPTOR and HIF1α. The siRNA knockdown and gene KO studies showed that DEPTOR and the HIF1-REDD1-TSC1 axis are responsible for MLN4924-induced autophagy via inhibiting mTORC1. Biologically, autophagy is a survival signal to tumor cells, and blockage of autophagy via siRNA knockdown, gene KO and small molecule inhibitor remarkably enhanced MLN4924-induced apoptosis. Our study reveals an uncharacterized mechanism of MLN4924 action and provides the proof-of-concept evidence for strategic drug combination of MLN4924 with an autophagy inhibitor for maximal killing of tumor cells via enhancing apoptosis.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI 48109, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: X
authors.initials: X
authors.lastname: Xiong
authors.forename: L
authors.initials: L
authors.lastname: Jia
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D003517:Cyclopentanes; C469991:DDIT4 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D011743:Pyrimidines; D034741:RNA, Small Interfering; C000624650:TSC1 protein, human; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C556139:DEPTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C539933:pevonedistat