Distinct perturbation of the translatome by the antidiabetic drug metformin

Metformin has been reported to lower cancer incidence among type II diabetics. Metformin exhibits antiproliferative and antineoplastic effects associated with inhibition of mammalian target of rapamycin complex 1 (mTORC1), but the mechanisms are poorly understood. We provide a unique genome-wide analysis of translational targets of canonical mTOR inhibitors (rapamycin and PP242) compared with metformin, revealing that metformin controls gene expression at the level of mRNA translation to an extent comparable to that of canonical mTOR inhibitors. Importantly, metformin's antiproliferative activity can be explained by selective translational suppression of mRNAs encoding cell-cycle regulators via the mTORC1/eukaryotic translation initiation factor 4E-binding protein pathway. Thus, metformin selectively inhibits translation of mRNAs encoding proteins that promote neoplastic proliferation, which should facilitate studies on metformin and related biguanides in cancer prevention and treatment.

[1]  M. Piccart,et al.  Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. , 2012, The New England journal of medicine.

[2]  J. Graff,et al.  Targeting the eukaryotic translation initiation factor 4E for cancer therapy. , 2008, Cancer research.

[3]  D. Sabatini,et al.  mTOR: from growth signal integration to cancer, diabetes and ageing , 2010, Nature Reviews Molecular Cell Biology.

[4]  S K Burley,et al.  Hierarchical phosphorylation of the translation inhibitor 4E-BP1. , 2001, Genes & development.

[5]  D. Guertin,et al.  The Pharmacology of mTOR Inhibition , 2009, Science Signaling.

[6]  M. Pollak.  The insulin and insulin-like growth factor receptor family in neoplasia: an update , 2012, Nature Reviews Cancer.

[7]  R. Myers,et al.  Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data , 2005, Nucleic acids research.

[8]  Giorgio Valle,et al.  The Gene Ontology project in 2008 , 2007, Nucleic Acids Res..

[9]  David Botstein,et al.  GO: : TermFinder--open source software for accessing Gene Ontology information and finding significantly enriched Gene Ontology terms associated with a list of genes , 2004, Bioinform..

[10]  Nicholas T. Ingolia,et al.  The translational landscape of mTOR signalling steers cancer initiation and metastasis , 2012, Nature.

[11]  N. Sonenberg,et al.  Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. , 2007, Cancer research.

[12]  R. Nadon,et al.  Identification of differential translation in genome wide studies , 2010, Proceedings of the National Academy of Sciences.

[13]  Robert Nadon,et al.  Anota: Analysis of Differential Translation in Genome-wide Studies , 2011, Bioinform..

[14]  B. Viollet,et al.  Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. , 2010, Cell metabolism.

[15]  Nahum Sonenberg,et al.  Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. , 2006, Cancer research.

[16]  I. Ben-Sahra,et al.  Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. , 2011, Cancer research.

[17]  M. Rigoulet,et al.  Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I* , 2000, The Journal of Biological Chemistry.

[18]  K. Inoki,et al.  TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival , 2003, Cell.

[19]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[20]  C. Chresta,et al.  Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR) , 2009, The Biochemical journal.

[21]  M. Owen,et al.  Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. , 2000, The Biochemical journal.

[22]  S. Formenti,et al.  Translational control in cancer , 2010, Nature Reviews Cancer.

[23]  F. Buttgereit,et al.  A hierarchy of ATP-consuming processes in mammalian cells. , 1995, The Biochemical journal.

[24]  A. Gingras,et al.  Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function , 1994, Nature.

[25]  J. Blenis,et al.  Molecular mechanisms of mTOR-mediated translational control , 2009, Nature Reviews Molecular Cell Biology.

[26]  D. Sabatini,et al.  An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1* , 2009, Journal of Biological Chemistry.

[27]  Robbie Loewith,et al.  Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2 , 2009, PLoS biology.

[28]  R. Shaw,et al.  LKB1 and AMP‐activated protein kinase control of mTOR signalling and growth , 2009, Acta physiologica.

[29]  S. Gygi,et al.  Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. , 1999, Genes & development.

[30]  M. Gerstein,et al.  Interrelating different types of genomic data, from proteome to secretome: 'oming in on function. , 2001, Genome research.

[31]  M. Pollak.  Metformin and Other Biguanides in Oncology: Advancing the Research Agenda , 2010, Cancer Prevention Research.

[32]  N. Sonenberg,et al.  p53-dependent translational control of senescence and transformation via 4E-BPs. , 2009, Cancer cell.

[33]  Alicja Wolk,et al.  Diabetes mellitus and risk of breast cancer: A meta‐analysis , 2007, International journal of cancer.

[34]  N. Sonenberg,et al.  mTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs , 2010, Science.

[35]  S. Larsson,et al.  Diabetes mellitus and risk of colorectal cancer: a meta-analysis. , 2005, Journal of the National Cancer Institute.

[36]  A. Rich,et al.  A multiple ribosomal structure in protein synthesis. , 1963, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Jennifer L. Osborn,et al.  Direct multiplexed measurement of gene expression with color-coded probe pairs , 2008, Nature Biotechnology.

[38]  B. Turk,et al.  AMPK phosphorylation of raptor mediates a metabolic checkpoint. , 2008, Molecular cell.

[39]  Rickard Sandberg,et al.  Improved precision and accuracy for microarrays using updated probe set definitions , 2007, BMC Bioinformatics.

[40]  I. Ben-Sahra,et al.  Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug? , 2010, Molecular Cancer Therapeutics.

[41]  M. Pollak,et al.  Insulin and insulin-like growth factor signalling in neoplasia , 2008, Nature Reviews Cancer.

[42]  Richard Simon,et al.  A random variance model for detection of differential gene expression in small microarray experiments , 2003, Bioinform..