PMID- 30794695
OWN - NLM
STAT- MEDLINE
DCOM- 20191121
LR  - 20211204
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 14
IP  - 2
DP  - 2019
TI  - Targeting mTOR and Src restricts hepatocellular carcinoma growth in a novel 
      murine liver cancer model.
PG  - e0212860
LID - 10.1371/journal.pone.0212860 [doi]
LID - e0212860
AB  - Liver cancer is a poor prognosis cancer with limited treatment options. To 
      develop a new therapeutic approach, we derived HCC cells from a known model of 
      murine hepatocellular carcinoma (HCC). We treated adiponectin (APN) knock-out 
      mice with the carcinogen diethylnitrosamine, and the resulting tumors were 7-fold 
      larger than wild-type controls. Tumors were disassociated from both genotypes and 
      their growth characteristics evaluated. A52 cells from APN KO mice had the most 
      robust growth in vitro and in vivo, and presented with pathology similar to the 
      parental tumor. All primary tumors and cell lines exhibited activity of the 
      mammalian target of Rapamycin (mTOR) and Src pathways. Subsequent combinatorial 
      treatment, with the mTOR inhibitor Rapamycin and the Src inhibitor Dasatinib 
      reduced A52 HCC growth 29-fold in vivo. Through protein and histological analyzes 
      we observed activation of these pathways in human HCC, suggesting that targeting 
      both mTOR and Src may be a novel approach for the treatment of HCC.
FAU - Walker, Sarah
AU  - Walker S
AD  - Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital 
      and University of Sydney, Westmead, Australia.
AD  - Gastroenterology and Hepatology Unit, The Canberra Hospital, Woden, Australia.
FAU - Wankell, Miriam
AU  - Wankell M
AD  - Department of Molecular and Cell Biology, Centre for Molecular Therapeutics, 
      James Cook University, Australian Institute of Tropical Health and Medicine, 
      Townsville, Australia.
FAU - Ho, Vikki
AU  - Ho V
AD  - Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital 
      and University of Sydney, Westmead, Australia.
FAU - White, Rose
AU  - White R
AD  - Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital 
      and University of Sydney, Westmead, Australia.
FAU - Deo, Nikita
AU  - Deo N
AD  - Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital 
      and University of Sydney, Westmead, Australia.
FAU - Devine, Carol
AU  - Devine C
AD  - Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital 
      and University of Sydney, Westmead, Australia.
FAU - Dewdney, Brittany
AU  - Dewdney B
AD  - Department of Molecular and Cell Biology, Centre for Molecular Therapeutics, 
      James Cook University, Australian Institute of Tropical Health and Medicine, 
      Townsville, Australia.
FAU - Bhathal, Prithi
AU  - Bhathal P
AD  - University of Melbourne, Victoria, Australia.
FAU - Govaere, Olivier
AU  - Govaere O
AD  - Translational Cell and Tissue Research, Department of Imaging and Pathology, 
      KULeuven and University Hospitals Leuven, Leuven, Belgium.
AD  - Liver Research Group, Institute of Cellular Medicine, The Medical School, 
      Newcastle University, Newcastle-upon-Tyne, United Kingdom.
FAU - Roskams, Tania
AU  - Roskams T
AD  - Translational Cell and Tissue Research, Department of Imaging and Pathology, 
      KULeuven and University Hospitals Leuven, Leuven, Belgium.
FAU - Qiao, Liang
AU  - Qiao L
AD  - Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital 
      and University of Sydney, Westmead, Australia.
FAU - George, Jacob
AU  - George J
AD  - Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital 
      and University of Sydney, Westmead, Australia.
FAU - Hebbard, Lionel
AU  - Hebbard L
AUID- ORCID: 0000-0002-7094-9065
AD  - Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital 
      and University of Sydney, Westmead, Australia.
AD  - Department of Molecular and Cell Biology, Centre for Molecular Therapeutics, 
      James Cook University, Australian Institute of Tropical Health and Medicine, 
      Townsville, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190222
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins pp60(c-src))
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RBZ1571X5H (Dasatinib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Carcinoma, Hepatocellular/*drug therapy/enzymology/pathology
MH  - Cell Line, Tumor
MH  - Dasatinib/*pharmacology
MH  - *Drug Delivery Systems
MH  - Humans
MH  - Liver Neoplasms, Experimental/*drug therapy/enzymology/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Proto-Oncogene Proteins pp60(c-src)/*antagonists & inhibitors/metabolism
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
PMC - PMC6386388
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/02/23 06:00
MHDA- 2019/11/22 06:00
PMCR- 2019/02/22
CRDT- 2019/02/23 06:00
PHST- 2018/12/10 00:00 [received]
PHST- 2019/02/12 00:00 [accepted]
PHST- 2019/02/23 06:00 [entrez]
PHST- 2019/02/23 06:00 [pubmed]
PHST- 2019/11/22 06:00 [medline]
PHST- 2019/02/22 00:00 [pmc-release]
AID - PONE-D-18-35322 [pii]
AID - 10.1371/journal.pone.0212860 [doi]
PST - epublish
SO  - PLoS One. 2019 Feb 22;14(2):e0212860. doi: 10.1371/journal.pone.0212860. 
      eCollection 2019.