Journal
CANCER SCIENCE
Volume 110, Issue 4, Pages 1256-1267Publisher
WILEY
DOI: 10.1111/cas.13952
Keywords
drug resistance; glucose starvation; metformin; mitochondria; multidrug resistance protein 1
Categories
Funding
- Basic Science Research Program through the National Research Foundation of Korea
- Ministry of Education, Science and Technology [2017R1A2B4008119]
- Brain Korea 21 Program, Research Institute of Veterinary Sciences, College of Veterinary Medicine, Seoul National University
- National Research Foundation of Korea [2017R1A2B4008119] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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