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|Ref Type||Journal Article|
|Authors||Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N|
|Title||Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells.|
|Date||2007 Nov 15|
|Abstract Text||Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|STK11 wild-type||Advanced Solid Tumor||sensitive||Metformin||Preclinical - Cell culture||Actionable||In a preclinical studies, Glucophage (metformin) inhibited cancer cell growth by activating the AMP kinase pathway in a variety of cancer cell lines that retained one functional allele of STK11 (PMID: 17062558, PMID: 18006825).||18006825 17062558|
|STK11 loss||Advanced Solid Tumor||no benefit||Metformin||Preclinical - Cell culture||Actionable||In a preclinical study, Glucophage (metformin) was unable to inhibit cancer cell growth in cancer cell lines with biallelic loss of STK11 (PMID: 17062558, PMID: 18006825).||18006825 17062558|