PMID- 22935614
OWN - NLM
STAT- MEDLINE
DCOM- 20130621
LR  - 20211203
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 20
IP  - 2
DP  - 2013 Feb
TI  - Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to 
      suppress the growth of liver cancer cells.
PG  - 235-47
LID - 10.1038/cdd.2012.113 [doi]
AB  - 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.
FAU - Yang, D
AU  - Yang D
AD  - Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 
      200032, China.
FAU - Li, L
AU  - Li L
FAU - Liu, H
AU  - Liu H
FAU - Wu, L
AU  - Wu L
FAU - Luo, Z
AU  - Luo Z
FAU - Li, H
AU  - Li H
FAU - Zheng, S
AU  - Zheng S
FAU - Gao, H
AU  - Gao H
FAU - Chu, Y
AU  - Chu Y
FAU - Sun, Y
AU  - Sun Y
FAU - Liu, J
AU  - Liu J
FAU - Jia, L
AU  - Jia L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120831
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (Carrier Proteins)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (RBX1 protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.1.1 (DEPTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - *Autophagy
MH  - Carcinoma, Hepatocellular/metabolism/*pathology
MH  - Carrier Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - *Cellular Senescence
MH  - Cyclin-Dependent Kinase Inhibitor p21/metabolism
MH  - G2 Phase Cell Cycle Checkpoints
MH  - Hep G2 Cells
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - Liver Neoplasms/metabolism/*pathology
MH  - M Phase Cell Cycle Checkpoints
MH  - RNA Interference
MH  - RNA, Small Interfering/metabolism
MH  - Survival Rate
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC3554346
EDAT- 2012/09/01 06:00
MHDA- 2013/06/25 06:00
PMCR- 2014/02/01
CRDT- 2012/09/01 06:00
PHST- 2012/09/01 06:00 [entrez]
PHST- 2012/09/01 06:00 [pubmed]
PHST- 2013/06/25 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - cdd2012113 [pii]
AID - 10.1038/cdd.2012.113 [doi]
PST - ppublish
SO  - Cell Death Differ. 2013 Feb;20(2):235-47. doi: 10.1038/cdd.2012.113. Epub 2012 
      Aug 31.