Open AccessGlucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1
Author(s) -
Hwang SungHyun,
Kim MyungChul,
Ji Sumin,
Yang Yeseul,
Jeong Yeji,
Kim Yongbaek
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13952
Subject(s) - metformin , autophagy , mitochondrion , apoptosis , biology , downregulation and upregulation , programmed cell death , mitochondrial permeability transition pore , membrane potential , multiple drug resistance , pharmacology , cancer research , microbiology and biotechnology , medicine , endocrinology , biochemistry , diabetes mellitus , gene , antibiotics
Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma ( HMM ) patients. The present 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 carbonyl cyanide m‐chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout 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.