Abstract
The biguanide drug metformin has been widely used for the treatment of type 2 diabetes, and there is evidence supporting the anticancer effect of metformin despite some controversy. Here, we report the growth inhibitory activity of metformin in the breast cancer (MCF-7) cells, both in vitro and in vivo, and the associated metabolic changes. In particular, a decrease in a well-known oncometabolite 2-hydroxyglutarate (2-HG) was discovered by a metabolomics approach. The decrease in 2-HG by metformin was accompanied by the reduction in histone methylation, consistent with the known tumorigenic mechanism of 2-HG. The relevance of 2-HG inhibition in breast cancer was also supported by a higher level of 2-HG in human breast cancer tissues. Genetic knockdown of PHGDH identified the PHGDH pathway as the producer of 2-HG in the MCF-7 cells that do not carry isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) mutations, the conventional producer of 2-HG. We also showed that metformin’s inhibitory effect on the PHGDH-2HG axis may occur through the regulation of the AMPK-MYC pathway. Overall, our results provide an explanation for the coherent pathway from complex I inhibition to epigenetic changes for metformin’s anticancer effect.
Highlights
Metformin belongs to the biguanide-class drugs and has been used for decades for the treatment of type 2 diabetes [1,2]
These may have to do with a decrease in cyclic AMP synthesis, and the resulting inhibition of protein kinase A (PKA), a key enzyme in glucagon signaling for the regulation of glycolysis and gluconeogenesis [11]
Using metabolomic profiling followed by mechanistic verification, we show that metformin suppresses the growth of the MCF-7 estrogen receptor-positive breast cancer cell line through the inhibition of 2-HG production by Phosphoglycerate dehydrogenase (PHGDH)
Summary
Metformin belongs to the biguanide-class drugs and has been used for decades for the treatment of type 2 diabetes [1,2]. The molecular mechanism of its antidiabetic effects has long been thought to involve the activation of AMP-activated protein kinase (AMPK) [9], but other studies, especially those involving animals lacking AMPK, strongly suggest the presence of alternative mechanisms [10,11]. These may have to do with a decrease in cyclic AMP (cAMP) synthesis, and the resulting inhibition of protein kinase A (PKA), a key enzyme in glucagon signaling for the regulation of glycolysis and gluconeogenesis [11]. PHGDH was shown to generate an oncometabolite 2-hydroxyglutarate (2-HG) in PHGDH-amplified triple-negative breast cancer cells [25], suggesting that this non-canonical activity of the enzyme may contribute to its tumorigenic role
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