PMID- 17483347
OWN - NLM
STAT- MEDLINE
DCOM- 20070618
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 9
DP  - 2007 May 1
TI  - Mammalian target of rapamycin activation impairs hepatocytic differentiation and 
      targets genes moderating lipid homeostasis and hepatocellular growth.
PG  - 4337-45
AB  - The mammalian target of rapamycin (mTOR) pathway, a major regulator of 
      translation, is frequently activated in hepatocellular carcinomas. We 
      investigated the effects of mTOR activation in the human HepaRG cells, which 
      possess potent hepatocytic differentiation capability. Differentiation of HepaRG 
      cells into functional and polarized hepatocyte-like cells correlated with a 
      decrease in mTOR and Akt activities. Stable cell lines expressing an activated 
      mutant of mTOR were generated. Sustained activation of mTOR impaired the 
      hepatocytic differentiation capability of these cells as shown by impaired 
      formation of bile canaliculi, absence of polarity, and reduced secretion of 
      alpha1-antitrypsin. An inhibitor of mTOR, rapamycin, was able to revert this 
      phenotype. Furthermore, increased mTOR activity in HepaRG cells resulted in their 
      resistance to the antiproliferative effects of transforming growth factor-beta1. 
      Profiling of polysome-bound transcripts indicated that activated mTOR 
      specifically targeted genes posttranscriptionally regulated on hepatocytic 
      differentiation. Three major biological networks targeted by activated mTOR were 
      identified: (a) cell death associated with tumor necrosis factor superfamily 
      members, IFNs and caspases; (b) lipid homeostasis associated with the 
      transcription factors PPARalpha, PPARdelta, and retinoid X receptor beta; and (c) 
      liver development associated with CCAAT/enhancer binding protein alpha and 
      hepatic mitogens. In conclusion, increased mTOR activity conferred a 
      preneoplastic phenotype to the HepaRG cells by altering the translation of genes 
      vital for establishing normal hepatic energy homeostasis and moderating 
      hepatocellular growth.
FAU - Parent, Romain
AU  - Parent R
AD  - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, 
      Washington 98109, USA.
FAU - Kolippakkam, Deepak
AU  - Kolippakkam D
FAU - Booth, Garrett
AU  - Booth G
FAU - Beretta, Laura
AU  - Beretta L
LA  - eng
GR  - DK066840/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Carcinoma, Hepatocellular/metabolism/pathology
MH  - Cell Differentiation/*physiology
MH  - Cell Growth Processes/physiology
MH  - Cell Line
MH  - Down-Regulation
MH  - Hepatocytes/cytology/metabolism/*physiology
MH  - Homeostasis/genetics
MH  - Humans
MH  - Lipid Metabolism/*genetics
MH  - Liver Neoplasms/metabolism/pathology
MH  - Polyribosomes/genetics/metabolism
MH  - Protein Kinases/biosynthesis/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA/genetics/metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
EDAT- 2007/05/08 09:00
MHDA- 2007/06/19 09:00
CRDT- 2007/05/08 09:00
PHST- 2007/05/08 09:00 [pubmed]
PHST- 2007/06/19 09:00 [medline]
PHST- 2007/05/08 09:00 [entrez]
AID - 67/9/4337 [pii]
AID - 10.1158/0008-5472.CAN-06-3640 [doi]
PST - ppublish
SO  - Cancer Res. 2007 May 1;67(9):4337-45. doi: 10.1158/0008-5472.CAN-06-3640.