Abstract
Despite the ability of cancer cells to survive glucose deprivation, most studies on anti-cancer effect of metformin explored its impact on glucose metabolism. No study ever examined whether its anti-cancer effect is reversible. Existing evidences warrant understanding of glucose-independent non-cytotoxic anti-proliferative effect of metformin to rationalize its role in liver cancer. Characterization of glucose-independent anti-proliferative metabolic effects of metformin as well as analysis of their reversibility in liver cancer cells. The dose-dependent effects of metformin on HepG2 cells were examined in presence and absence of glucose. The longitudinal evolution of metabolome was analyzed along with gene and protein expression as well as their correlations with and reversibility of cellular phenotype and metabolic signatures. Metformin concentrations up to 2.5mM were found to be anti-proliferative irrespective of presence of glucose without significant increase in cytotoxicity. Apart from mitochondrial impairment, derangement of fatty acid desaturation, one-carbon, glutathione, and polyamine metabolism were associated with metformin treatment irrespective of glucose supplementation. Depletion of pantothenic acid, downregulation of essential amino acid uptake and metabolism alongside purine salvage were identified as novel glucose-independent effects of metformin. These were significantly correlated with cMyc expression and reduction in proliferation. Rescue experiments established reversibility upon metformin withdrawal and tight association between proliferation, metabotype, and cMyc expression. The derangement of multiple glucose-independent metabolic pathways, which are often upregulated in therapy-resistant cancer, and concomitant cMyc downregulation coordinately contribute to the anti-proliferative effect of metformin in liver cancer cells. These are reversible and may influence its therapeutic utility.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
