PMID- 26278819
OWN - NLM
STAT- MEDLINE
DCOM- 20151127
LR  - 20211203
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 465
IP  - 3
DP  - 2015 Sep 25
TI  - Autophagy inhibition sensitizes KU-0063794-mediated anti-HepG2 hepatocellular 
      carcinoma cell activity in vitro and in vivo.
PG  - 494-500
LID - S0006-291X(15)30435-6 [pii]
LID - 10.1016/j.bbrc.2015.08.045 [doi]
AB  - Recent studies have indicated that mammalian target of rapamycin (mTOR) signaling 
      has a critical role in the pathogenesis of hepatocellular carcinoma (HCC). In the 
      current study, we investigated the activity of KU-0063794, a novel mTOR kinase 
      inhibitor, against HepG2 HCC cells. Our results demonstrated that KU-0063794 
      blocked mTOR complex 1/2 (mTORC1/2) activation, and downregulated mTOR-regulated 
      genes (Cyclin D1 and hypoxia-inducible factor 1alpha) in HepG2 cells. Consequently, 
      KU-0063794 induced significant anti-survival and pro-apoptotic activities against 
      HepG2 cells. When analyzing the possible KU-0063794-resistance factors, we showed 
      that KU-0063794 induced cyto-protective autophagy activation in HepG2 cells, 
      evidenced by GFP-light chain 3B (LC3B) puncta formation, p62 degradation, 
      Beclin-1 expression and LC3B-I to LC3B-II conversion. Correspondingly, autophagy 
      inhibitors, including bafliomycin A1, 3-methyladenine (3-MA) and chloroquine, 
      dramatically enhanced KU-0063794-induced cytotoxicity against HepG2 cells. 
      Further, RNAi knockdown of Beclin-1 also increased KU-0063794 sensitivity in 
      HepG2 cells. In vivo, oral administration of KU-0063794 repressed HepG2 xenograft 
      growth in severe combined immunodeficient (SCID) mice, and its activity was 
      further enhanced with co-administration of the autophagy inhibitor 3-MA. In 
      summary, KU-0063794 inhibits HepG2 cell growth in vitro and in vivo, its activity 
      could be further enhanced with autophagy inhibition.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Yongxi, Tong
AU  - Yongxi T
AD  - Department of Infectious Disease, Zhejiang Province People's Hospital, Hangzhou, 
      China.
FAU - Haijun, Huang
AU  - Haijun H
AD  - Department of Infectious Disease, Zhejiang Province People's Hospital, Hangzhou, 
      China.
FAU - Jiaping, Zheng
AU  - Jiaping Z
AD  - Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou, 
      China.
FAU - Guoliang, Shao
AU  - Guoliang S
AD  - Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou, 
      China.
FAU - Hongying, Pan
AU  - Hongying P
AD  - Department of Infectious Disease, Zhejiang Province People's Hospital, Hangzhou, 
      China. Electronic address: PANHongyingHZ@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150814
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Morpholines)
RN  - 0 (Pyrimidines)
RN  - 81HJG228AB (Ku 0063794)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Autophagy/drug effects
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Hep G2 Cells
MH  - Humans
MH  - Mice
MH  - Mice, SCID
MH  - Morpholines/*administration & dosage
MH  - Neoplasms, Experimental/*drug therapy/metabolism/*pathology
MH  - Pyrimidines/*administration & dosage
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/*metabolism
OTO - NOTNLM
OT  - Autophagy
OT  - Hepatocellular carcinoma
OT  - KU-0063794
OT  - Sensitization
OT  - mTOR
EDAT- 2015/08/19 06:00
MHDA- 2015/12/15 06:00
CRDT- 2015/08/18 06:00
PHST- 2015/08/07 00:00 [received]
PHST- 2015/08/11 00:00 [accepted]
PHST- 2015/08/18 06:00 [entrez]
PHST- 2015/08/19 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
AID - S0006-291X(15)30435-6 [pii]
AID - 10.1016/j.bbrc.2015.08.045 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2015 Sep 25;465(3):494-500. doi: 
      10.1016/j.bbrc.2015.08.045. Epub 2015 Aug 14.