Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner

Metformin is a widely prescribed medication whose mechanism of action is not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing the risk of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormalities in placental development including impairments in trophoblast differentiation. Given that metformin impacts cellular differentiation events in other systems, we assessed metformin's impact on trophoblast metabolism and differentiation. Using established cell culture models of trophoblast differentiation, oxygen consumption rates and relative metabolite abundance were determined following 200 mu M (therapeutic range) and 2000 mu M (supra-therapeutic range) metformin treatment using Seahorse and mass-spectrometry approaches. While no differences in oxygen consumption rates or relative metabolite abundance were detected between vehicle and 200 mu M metformin-treated cells, 2000 mu M metformin impaired oxidative metabolism and increased the abundance of lactate and TCA cycle intermediates, alpha-ketoglutarate, succinate, and malate. Examining differentiation, treatment with 2000 mu M, but not 200 mu M metformin, impaired HCG production and expression of multiple trophoblast differentiation markers. Overall, this work suggests that supra-therapeutic concentrations of metformin impair trophoblast metabolism and differentiation whereas metformin concentrations in the therapeutic range do not strongly impact these processes.

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The study found that the inhibitory effect of melanoma on the growth and invasion of skin cancer cells may be related to the regulation of proliferation and apoptosis of skin cancer cells by melanoma cells through the p38 signaling pathway.