Metformin Represses Glucose Starvation Induced Autophagic Response in Microvascular Endothelial Cells and Promotes Cell Death
Abstract
Metformin, the most frequently administered drug for the treatment of type 2 diabetes, is being investigated for its potential in the treatment of various types of cancer; however, the cellular basis for this putative anti-cancer action remains controversial. In the current study we examined the effect of metformin on endoplasmic reticulum (ER) stress and autophagy in glucose-starved micro-vascular endothelial cells (MECs). The rationale for our experimental protocol is that in a growing tumor MECs are subjected to hypoxia and nutrient/glucose starvation that results from the reduced supply and relatively high consumption of glucose. Mouse MECs (MMECs) were glucose-starved for up to 48h in the absence or presence of metformin (50μM and 2mM) and the status of ER stress, autophagic, cell survival and apoptotic markers were assessed. Activation of ER stress and autophagy was observed in glucose starved MECs as evidenced by the significant increase in the levels of ER stress and autophagic markers while accumulation of LC3B stained punctae in the MECs confirmed autophagic activation. Treatment with 2mM metformin, independent of AMPK, significantly reversed glucose starvation induced ER stress and autophagy in MECs, but, at 24h, did not decrease cell viability; however, at 48h, persistent ER stress and metformin associated inhibition of autophagy decreased cell viability, caused cell cycle arrest in G2/M and increased the number of cells in the sub-G0/G1 phase of cell cycle. Treatment with metformin reduced phosphorylation of Akt and mTOR and inhibited downstream targets of mTOR. Our findings support the argument that treatment with metformin when used in combination with glycolytic inhibitors will inhibit pro-survival autophagy and promote cell death and potentially prove to be the basis for an effective anti-cancer strategy.
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The effects of metformin to inhibit autophagy were only seen following a 48-hour incubation with 2 mM metformin, and lower concentrations in the therapeutic range, including 50 μM, were ineffective.
“The effects of metformin to inhibit autophagy were only seen following a 48-hour incubation with 2 mM metformin, and lower concentrations that are in the therapeutic range, including 50 μM, were ineffective (235).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [235]
Under conditions when tumor microvascular endothelial cells in culture are exposed to glucose starvation, metformin inhibits autophagy via inhibition of the mTOR pathway and a partially AMPK-independent mechanism.
“However, under conditions when tumor microvascular endothelial cells in culture are exposed to glucose starvation, metformin inhibits autophagy via inhibition of the mTOR pathway and a partially AMPK-independent mechanism in (235).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [235]
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Metformin Decreases Hyaluronan Synthesis by Vascular Smooth Muscle Cells
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- Authors
- Samuel, S. M., Ghosh, S., Majeed, Y., Arunachalam, G., Emara, M. M., Ding, H., & Triggle, C. R.
- Affiliations
- Weill Cornell Medical College in Qatar (QA)
- Hamad bin Khalifa University (QA)
- Corresponding author
- Triggle, Chris R.
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 132
- Pages
- 118-132
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W2594389818
- Cited by
- 37
- References
- 69
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 8 · 2018: 6 · 2017: 2
- FWCI
- 2.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Priorities Research Program (04-910-3-244)
- Junior Scientist Research Experience Program (03-016-3-009)
- Qatar National Research Fund
- Qatar Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- metformin, glucose deprivation, autophagy, endoplasmic reticulum stress, microvascular endothelial cells, apoptosis, cell cycle arrest, mTOR inhibition, Akt phosphorylation, cancer therapy, type 2 diabetes, glycolysis inhibitors, tumor hypoxia
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Culture Media, Endothelium, Vascular, Glucose, Hypoglycemic Agents, Metformin, Cell Death, Mice, Microvessels, Endoplasmic Reticulum Stress
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