Distinct perturbation of the translatome by the antidiabetic drug metformin

Ola Larsson, Masahiro Morita, Ivan Topisirovic, Tommy Alain, Marie Jose Blouin, Michael Pollak, Nahum Sonenberg

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

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 themechanisms 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.

Original languageEnglish (US)
Pages (from-to)8977-8982
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number23
DOIs
StatePublished - Jun 5 2012
Externally publishedYes

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Metformin
Hypoglycemic Agents
Protein Biosynthesis
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
Biguanides
Sirolimus
Antineoplastic Agents
Neoplasms
Cell Cycle
Carrier Proteins
Genome
Gene Expression
Messenger RNA
Incidence
Proteins

Keywords

  • Polysome-microarray
  • Posttranscriptional regulation
  • Translatomics

ASJC Scopus subject areas

  • General

Cite this

Distinct perturbation of the translatome by the antidiabetic drug metformin. / Larsson, Ola; Morita, Masahiro; Topisirovic, Ivan; Alain, Tommy; Blouin, Marie Jose; Pollak, Michael; Sonenberg, Nahum.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 23, 05.06.2012, p. 8977-8982.

Research output: Contribution to journalArticle

Larsson, Ola ; Morita, Masahiro ; Topisirovic, Ivan ; Alain, Tommy ; Blouin, Marie Jose ; Pollak, Michael ; Sonenberg, Nahum. / Distinct perturbation of the translatome by the antidiabetic drug metformin. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 23. pp. 8977-8982.
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