Proc. Natl. Acad. Sci. USA, published online 18 May 2012, doi:10.1073/pnas.1201689109

Metformin, an activator of AMP kinase and a widely used antidiabetic drug, has been associated with antiproliferative effects through interference with the mammalian target of rapamycin complex 1 (mTORC1) anabolic pathway. Larsson et al. now explore the mechanisms by which metformin counteracts the mTORC1 pathway. The authors treated MCF7 cells with metformin or two known mTORC1 inhibitors and observed inhibition of the translational regulator 4E-BP and concomitant reduction in the rate of translational initiation. Although the drugs had minimal effects on gene expression and total cytoplasmic mRNA levels, genome-wide analyses of polysome-associated mRNAs present in metformin- or mTORC1 inhibitor–treated cells showed a dramatic decrease in the levels of some translated mRNAs. Gene ontology analyses of the affected mRNAs revealed a partial overlap between metformin- and mTORC1 inhibitor–treated cells. The overlapping mRNAs were enriched for those encoding proteins with cell-cycle functions. The authors verified the effects of the drugs on the translation of specific cell cycle regulators, cyclin E2 and ornithine decarboxylase 1 (ODC1). 4E-BP knockout cells were partially resistant to metformin-mediated inhibition of proliferation and translation of cell cycle regulators. In sum, the authors showed that metformin specifically inhibits the translation of mRNAs that regulate cell cycle through inhibition of the 4E-BP translation protein.