Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells
Bibliographic record
Abstract
// Mamatha Bhat 1, 2, 3 , Akiko Yanagiya 1 , Tyson Graber 4 , Nataliya Razumilava 3, 5 , Steve Bronk 3 , Domenick Zammit 1 , Yunhao Zhao 6 , Chadi Zakaria 1 , Peter Metrakos 7 , Michael Pollak 6 , Nahum Sonenberg 1 , Gregory Gores 3 , Maritza Jaramillo 8 , Masahiro Morita 1, * and Tommy Alain 4, * 1 Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada 2 Division of Gastroenterology, University Health Network and University of Toronto, Toronto, Canada, USA 3 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 4 Children’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada 5 Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA 6 Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal, Canada 7 Department of Surgery, McGill University Health Centre, Montreal, Canada 8 INRS Institut Armand-Frappier Research Centre, Laval, Quebec, Canada * These authors have contributed equally to this work Correspondence to: Mamatha Bhat, email: mamatha.bhat@uhn.ca Masahiro Morita, email: masahiro.morita@mail.mcgill.ca Tommy Alain, email: tommy@arc.cheo.ca Keywords: metformin, hepatocellular carcinoma, mRNA translation, mTORC1, 4E-BPs Received: October 04, 2015     Accepted: July 06, 2016     Published: July 18, 2016 ABSTRACT 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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".