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Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells

Bhat, Mamatha; Yanagiya, Akiko; Graber, Tyson; Razumilava, Nataliya; Bronk, Steve; Zammit, Domenick; Zhao, Yunhao; Metrakos, Peter; Pollak, Michael; Sonenberg, Nahum; Gores, Gregory; Jaramillo, Maritza; Morita, Masahiro; Alain, Tommy (2017). Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells Oncotarget , vol. 8 , nº 31. p. 50542-50556. DOI: 10.18632/oncotarget.10671.

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Résumé

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.

Type de document: Article
Mots-clés libres: 4E-BPs; hepatocellular carcinoma; mRNA translation; mTORC1; metformin
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 27 sept. 2017 15:56
Dernière modification: 27 sept. 2017 15:56
URI: http://espace.inrs.ca/id/eprint/5944

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