Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein1

Summary

Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on survival rate of human malignant mesothelioma (HMM) patients. This study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose starved HMM cells had enhanced resistance to metformin demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly Mdr1 was significantly upregulated in mitochondria, but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with CCCP, a MMP depolarization inducer. Furthermore, apoptosis and autophagy was increased in MDR1 KO HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy.

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