PMID- 28881582
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20170925
LR  - 20220331
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 31
DP  - 2017 Aug 1
TI  - Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in 
      hepatocellular carcinoma cells.
PG  - 50542-50556
LID - 10.18632/oncotarget.10671 [doi]
AB  - Metformin inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling 
      pathway, which is frequently upregulated in hepatocellular carcinoma (HCC). 
      Metformin has also been shown to induce apoptosis in this cancer. Here, we 
      investigate whether metformin-induced apoptosis in HCC is mediated by the 
      downstream mTORC1 effectors eukaryotic initiation factor 4E and (eIF4E)-binding 
      proteins (4E-BPs). Further, we ask whether changes in 4E-BPs activity during 
      metformin treatment negatively regulate translation of the anti-apoptotic myeloid 
      cell leukemia 1 (Mcl-1) mRNA. A genetic HCC mouse model was employed to assess 
      the ability of metformin to reduce tumor formation, induce apoptosis, and control 
      4E-BP1 activation and Mcl-1 protein expression. In parallel, the HCC cell line 
      Huh7 was transduced with scrambled shRNA (control) or shRNAs targeting 4E-BP1 and 
      4E-BP2 (4E-BP knock-down (KD)) to measure differences in mRNA translation, 
      apoptosis, and Mcl-1 protein expression after metformin treatment. In addition, 
      immunohistochemical staining of eIF4E and 4E-BP1 protein levels was addressed in 
      a HCC patient tissue microarray. We found that metformin decreased HCC tumor 
      burden, and tumor tissues showed elevated apoptosis with reduced Mcl-1 and 
      phosphorylated 4E-BP1 protein levels. In control but not 4E-BP KD Huh7 cells, 
      metformin induced apoptosis and repressed Mcl-1 mRNA translation and protein 
      levels. Immunostaining of HCC patient tumor tissues revealed a varying ratio of 
      eIF4E/4E-BP1 expression. Our results propose that metformin induces apoptosis in 
      mouse and cellular models of HCC through activation of 4E-BPs, thus tumors with 
      elevated expression of 4E-BPs may display improved clinical chemopreventive 
      benefit of metformin.
FAU - Bhat, Mamatha
AU  - Bhat M
AD  - Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, 
      Canada.
AD  - Division of Gastroenterology, University Health Network and University of 
      Toronto, Toronto, Canada, USA.
AD  - Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
FAU - Yanagiya, Akiko
AU  - Yanagiya A
AD  - Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, 
      Canada.
FAU - Graber, Tyson
AU  - Graber T
AD  - Children's Hospital of Eastern Ontario Research Institute, Department of 
      Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, 
      Canada.
FAU - Razumilava, Nataliya
AU  - Razumilava N
AD  - Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
AD  - Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.
FAU - Bronk, Steve
AU  - Bronk S
AD  - Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
FAU - Zammit, Domenick
AU  - Zammit D
AD  - Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, 
      Canada.
FAU - Zhao, Yunhao
AU  - Zhao Y
AD  - Departments of Medicine and Oncology, Lady Davis Institute for Medical Research 
      and Segal Cancer Center, Montreal, Canada.
FAU - Zakaria, Chadi
AU  - Zakaria C
AD  - Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, 
      Canada.
FAU - Metrakos, Peter
AU  - Metrakos P
AD  - Department of Surgery, McGill University Health Centre, Montreal, Canada.
FAU - Pollak, Michael
AU  - Pollak M
AD  - Departments of Medicine and Oncology, Lady Davis Institute for Medical Research 
      and Segal Cancer Center, Montreal, Canada.
FAU - Sonenberg, Nahum
AU  - Sonenberg N
AD  - Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, 
      Canada.
FAU - Gores, Gregory
AU  - Gores G
AD  - Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
FAU - Jaramillo, Maritza
AU  - Jaramillo M
AD  - INRS Institut Armand-Frappier Research Centre, Laval, Quebec, Canada.
FAU - Morita, Masahiro
AU  - Morita M
AD  - Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, 
      Canada.
FAU - Alain, Tommy
AU  - Alain T
AD  - Children's Hospital of Eastern Ontario Research Institute, Department of 
      Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, 
      Canada.
LA  - eng
GR  - R01 DK059427/DK/NIDDK NIH HHS/United States
GR  - R56 DK059427/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20160718
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5584165
OTO - NOTNLM
OT  - 4E-BPs
OT  - hepatocellular carcinoma
OT  - mRNA translation
OT  - mTORC1
OT  - metformin
COIS- CONFLICTS OF INTEREST The authors have no potential conflict of interest to 
      report.
EDAT- 2016/07/18 00:00
MHDA- 2016/07/18 00:01
PMCR- 2017/08/01
CRDT- 2017/09/09 06:00
PHST- 2015/10/04 00:00 [received]
PHST- 2016/07/06 00:00 [accepted]
PHST- 2017/09/09 06:00 [entrez]
PHST- 2016/07/18 00:00 [pubmed]
PHST- 2016/07/18 00:01 [medline]
PHST- 2017/08/01 00:00 [pmc-release]
AID - 10671 [pii]
AID - 10.18632/oncotarget.10671 [doi]
PST - epublish
SO  - Oncotarget. 2016 Jul 18;8(31):50542-50556. doi: 10.18632/oncotarget.10671. 
      eCollection 2017 Aug 1.