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2017 ; 8
(31
): 50542-50556
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Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in
hepatocellular carcinoma cells
#MMPMID28881582
Bhat M
; Yanagiya A
; Graber T
; Razumilava N
; Bronk S
; Zammit D
; Zhao Y
; Zakaria C
; Metrakos P
; Pollak M
; Sonenberg N
; Gores G
; Jaramillo M
; Morita M
; Alain T
Oncotarget
2017[Aug]; 8
(31
): 50542-50556
PMID28881582
show ga
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.
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