PMID- 25628925
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150128
LR  - 20201001
IS  - 2156-6976 (Print)
IS  - 2156-6976 (Electronic)
IS  - 2156-6976 (Linking)
VI  - 5
IP  - 1
DP  - 2015
TI  - Dramatic antitumor effects of the dual mTORC1 and mTORC2 inhibitor AZD2014 in 
      hepatocellular carcinoma.
PG  - 125-39
AB  - The mammalian target of rapamycin (mTOR) has emerged as a critical effector in 
      cell growth, proliferation, survival, angiogenesis, and autophagy through direct 
      interaction with mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2). The mTOR 
      axis is aberrantly activated in about 50% of human hepatocellular carcinoma (HCC) 
      cases and thus has become an attractive target for drug development in this 
      disease. Allosteric inhibitors of mTORC1, rapamycin and its derivatives have been 
      used to study in patients with HCC but have not shown significant clinical 
      utility, likely because of the lack of inhibition of mTORC2. In the present 
      study, we describe that AZD2014, a small molecular ATP-competitive inhibitor of 
      mTOR, was a highly potent inhibitor of mTORC1 and mTORC2 in human HCC cells, 
      which led to a more thorough inhibition of mTORC1 than rapamycin, and the 
      inhibition of mTORC2 prevented the feedback activation of AKT signaling. Compared 
      with rapamycin, AZD2014 resulted in more profound proliferation suppression, 
      apoptosis, cell cycle arrest, and autophagy in HCC cells. Notably, we found 
      blockage of both mTORC1 and mTORC2 by AZD2014 to be more efficacious than 
      blockage of mTORC1 alone by rapamycin in inhibiting the migration, invasion and 
      EMT progression of HCC cells. In conclusion, our current results highlight 
      mechanistic differentiation between rapamycin and AZD2014 in targeting cancer 
      cell proliferation, cell cycle, apoptosis, autophagy, migration, invasion and EMT 
      progression, and provide support for further investigation of AZD2014 as an 
      antitumor agent for the treatment of HCC in clinic.
FAU - Liao, Hui
AU  - Liao H
AD  - Department of Hepatobiliary Surgery, Nanfang Hospital Affiated to Southern 
      Medical University Guangzhou, Guangdong, PR China.
FAU - Huang, Yu
AU  - Huang Y
AD  - Department of Laboratory Medicine, Nanfang Hospital Affiated to Southern Medical 
      University Guangzhou, Guangdong, PR China.
FAU - Guo, Botang
AU  - Guo B
AD  - Department of Hepatobiliary Surgery, Nanfang Hospital Affiated to Southern 
      Medical University Guangzhou, Guangdong, PR China.
FAU - Liang, Bo
AU  - Liang B
AD  - Department of Hepatobiliary Surgery, Nanfang Hospital Affiated to Southern 
      Medical University Guangzhou, Guangdong, PR China.
FAU - Liu, Xincheng
AU  - Liu X
AD  - Department of Hepatobiliary Surgery, Nanfang Hospital Affiated to Southern 
      Medical University Guangzhou, Guangdong, PR China.
FAU - Ou, Huohui
AU  - Ou H
AD  - Department of Hepatobiliary Surgery, Nanfang Hospital Affiated to Southern 
      Medical University Guangzhou, Guangdong, PR China.
FAU - Jiang, Chenglong
AU  - Jiang C
AD  - Department of Hepatobiliary Surgery, Nanfang Hospital Affiated to Southern 
      Medical University Guangzhou, Guangdong, PR China.
FAU - Li, Xianghong
AU  - Li X
AD  - Department of Hepatobiliary Surgery, Nanfang Hospital Affiated to Southern 
      Medical University Guangzhou, Guangdong, PR China.
FAU - Yang, Dinghua
AU  - Yang D
AD  - Department of Hepatobiliary Surgery, Nanfang Hospital Affiated to Southern 
      Medical University Guangzhou, Guangdong, PR China.
LA  - eng
PT  - Journal Article
DEP - 20141215
PL  - United States
TA  - Am J Cancer Res
JT  - American journal of cancer research
JID - 101549944
PMC - PMC4300717
OTO - NOTNLM
OT  - AZD2014
OT  - EMT
OT  - Hepatocellular carcinoma
OT  - autophagy
OT  - mTOR kinase inhibitor
EDAT- 2015/01/30 06:00
MHDA- 2015/01/30 06:01
PMCR- 2014/12/15
CRDT- 2015/01/29 06:00
PHST- 2014/10/08 00:00 [received]
PHST- 2014/11/18 00:00 [accepted]
PHST- 2015/01/29 06:00 [entrez]
PHST- 2015/01/30 06:00 [pubmed]
PHST- 2015/01/30 06:01 [medline]
PHST- 2014/12/15 00:00 [pmc-release]
PST - epublish
SO  - Am J Cancer Res. 2014 Dec 15;5(1):125-39. eCollection 2015.