Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 23, Pages 8977-8982Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1201689109
Keywords
polysome-microarray; posttranscriptional regulation; translatomics
Categories
Funding
- Canadian Cancer Society Research Institute (CCSR)
- Canadian Institute of Health Research (CIHR)
- Swedish Research Council
- Swedish Cancer Foundation
- Cancer Society in Stockholm
- Jeansson Foundation
- Ake Wiberg Foundation
- Terry Fox Research Institute
- Uehara Memorial foundation
- Japan Society for the Promotion of Science
- Brain Tumour Foundation of Canada
- CCSR
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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.
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