title: Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to suppress the growth of liver cancer cells.
abstract: Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell senescence and/or apoptosis. However, it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL. Moreover, the role of ROC1 in liver cancer remains elusive. In this study, we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin (mTOR) activity due to accumulation of mTOR-inhibitory protein Deptor, a substrate of CRL. Consistently, Deptor knockdown significantly blocked autophagy response upon ROC1 silencing. Biologically, autophagy response upon ROC1 silencing was a survival signal, and blockage of autophagy pathway sensitized cancer cells to apoptosis. Finally, we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas, which is associated with poor prognosis of liver cancer patients. These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis.
authors.affiliation: Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: Z
authors.initials: Z
authors.lastname: Luo
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Zheng
authors.forename: H
authors.initials: H
authors.lastname: Gao
authors.forename: Y
authors.initials: Y
authors.lastname: Chu
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Jia
mesh_terms: D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D059566:M Phase Cell Cycle Checkpoints; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; C479529:RBX1 protein, human; D034741:RNA, Small Interfering; C556139:DEPTOR protein, human; D058570:TOR Serine-Threonine Kinases