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Distinct perturbation of the translatome by the antidiabetic drug metformin.

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 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.

SUBMITTER: Larsson O

PROVIDER: S-EPMC3384216 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Distinct perturbation of the translatome by the antidiabetic drug metformin.

Larsson Ola O Morita Masahiro M Topisirovic Ivan I Alain Tommy T Blouin Marie-Jose MJ Pollak Michael M Sonenberg Nahum N

Proceedings of the National Academy of Sciences of the United States of America 20120518 23

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 exte ...[more]

PMID: 22611195

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Project description:BackgroundMetformin has been linked to improved survival among diabetic prostate cancer (PCa) patients, while hyperinsulinemia and insulin usage has been related to worse prognosis.ObjectiveTo evaluate the association of metformin and other antidiabetic drugs with PCa death and androgen deprivation therapy (ADT).Design setting and participantsThe study cohort included 14 424 men who underwent radical prostatectomy in Finland during 1995-2013. Cases were identified, and clinical data were collected from patient files and national registries using personal identification numbers.InterventionInformation on the use of each antidiabetic drug during 1995-2014 was collected from prescription registry of the Social Insurance Institution of Finland.Outcome measurements and statistical analysisThe risks of PCa death and initiation of ADT were analyzed by antidiabetic drug use with the Cox regression method. Each antidiabetic drug group was analyzed separately to model simultaneous usage. Pre- and postdiagnostic uses were analyzed separately.Results and limitationsPrediagnostic use of antidiabetic drugs in general had no association with the risk of PCa death. Prediagnostic use of metformin was related to a reduced risk of ADT initiation (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59-0.96), while high-dose insulin users had an increased risk. Overall, antidiabetic drug use after PCa diagnosis was associated with an elevated risk of PCa death. Only postdiagnostic metformin use was associated with reduced risks of PCa death (HR 0.47, 95% CI 0.30-0.76) and ADT initiation compared with nonusers. Study limitations are missing information on glycemic control, smoking, living or exercise habits, prostate-specific antigen, and Gleason score.ConclusionsAmong surgically treated PCa patients, use of metformin was associated with improved disease-specific survival, while insulin and insulin secretagogues were associated with poor survival. Metformin might be a favorable diabetes treatment among men with PCa.Patient summaryIn this Finnish nationwide study, we found that the risks of prostate cancer death and cancer progression are lowered among metformin users, but not among other antidiabetic drug users. Metformin might be a favorable treatment choice for diabetes in men with prostate cancer.

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Distinct perturbation of the translatome by the antidiabetic drug metformin.

Publications

Distinct perturbation of the translatome by the antidiabetic drug metformin.

Similar Datasets

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