Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1

Our plain-English summary of Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1, by S.H. Hwang, M.C. Kim, S. Ji, et al (Cancer Science, 2019).

The study

• Authors: S.H. Hwang, M.C. Kim, S. Ji, Y. Yang, Y. Jeong, Y. Kim
• Journal: Cancer Science
• Published: 2019;110(4):1256-1267
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This was a laboratory study of cells grown in dishes, not of people; asbestos was mentioned only as background. The authors asked why metformin, a diabetes drug, may fail against human malignant mesothelioma when glucose is scarce. They grew two mesothelioma cell lines (MS1 and H513) and a benign mesothelial line (Met-5A) at 0, 1, 5 or 10 mmol/L glucose, and treated the mesothelioma lines with 5 mmol/L metformin. Met-5A cells did not survive 3 days without enough glucose, while the mesothelioma cells did. Metformin significantly reduced viability of mesothelioma cells grown with 5 or 10 mmol/L glucose but had little effect on glucose-starved cells. Glucose-starved cells given metformin also showed less apoptosis (programmed cell death) and less autophagy. In those cells, MDR1 mRNA, the message for a drug-pumping protein, was approximately 10-fold higher than in cells grown in complete medium; in MS1 cells, MDR1 protein sat mainly in mitochondria. When MDR1 was knocked out, metformin reduced viability and increased apoptosis in glucose-starved cells. The authors concluded that mitochondrial MDR1 helped glucose-starved mesothelioma cells resist metformin.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell culture experiment
• Who was studied: Two human malignant mesothelioma cell lines (MS1 and NIH-513, called H513) and one benign transformed mesothelial cell line (Met-5A). No human or animal subjects.
• Exposure: All three cell lines were grown in medium with 0, 1, 5 or 10 mmol/L glucose. The mesothelioma cell lines were grown at these glucose levels for 2 days, then treated with 5 mmol/L metformin for 1 day. Asbestos exposure was not studied.
• Main results:
  • Benign Met-5A cells did not survive 3 days under glucose-deficient conditions. The mesothelioma cell lines MS1 and H513 did survive.
  • Metformin significantly decreased the viability of mesothelioma cells grown with 5 and 10 mmol/L glucose. It had minimal effect on cells precultured under glucose-deficient conditions.
  • In glucose-deficient mesothelioma cells, metformin suppressed total apoptosis and significantly suppressed autophagic activity, compared with cells in complete medium.
  • In glucose-starved mesothelioma cells treated with metformin, MDR1 mRNA expression was approximately 10-fold higher than in cells cultured in complete medium.
  • Membrane MDR1 levels were not significantly changed. In MS1 cells most MDR1 was in the mitochondria. In H513 cells MDR1 was found in all subcellular fractions.
  • ATP levels fell with glucose starvation or metformin. Glucose-starved cells treated with metformin showed mitochondrial membrane potential hyperpolarization, especially MS1 cells.
  • Treatment with CCCP, a drug that depolarizes mitochondria, suppressed both the increased membrane potential and the mitochondrial MDR1 in glucose-starved, metformin-treated cells.
  • In MDR1 knockout mesothelioma cells under glucose starvation, metformin significantly reduced viability and increased apoptosis, unlike in parental cells.
• The authors' conclusion: The authors concluded that overexpressed MDR1 in damaged mitochondria rescued glucose-starved mesothelioma cells from metformin. They suggested MDR1 could be a target for improving metformin's effect.
• Limitations the authors state:
  • The authors stated that further research is needed on the relationship between autophagy and MDR1.
  • The authors stated that how MDR1 expression and localization are controlled in mesothelioma cells is not yet clear.
  • The authors stated that the role of ABCG2 in metformin resistance needs further study.

Topics

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Apoptosis.

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