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Analysis of glucose-independent metabolic pathways associated with anti-proliferative effect of metformin and their reversibility in liver cancer cells

ABSTRACT:

Several studies indicated anti-cancer effects of metformin in liver cancer. This was attributed to the activation of LKB-AMPK axis, which is associated with anti-hyperglycaemic effect and cytotoxicity. However, glucose- and central carbon-independent effects of metformin and their reversibility remain unexplored. 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 ≤2.5mM were found to be non-cytotoxic but anti-proliferative irrespective of presence of glucose. Mitochondrial impairment along with derangement of one-carbon, glutathione and polyamine metabolism was associated with non-cytotoxic metformin treatment irrespective of glucose supplementation. Depletion of pantothenic acid, upregulation of fatty acid desaturation and downregulation of essential amino acid uptake, metabolism and 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. Taken together, derangement of novel glucose-independent pathways and concomitant cMyc downregulation coordinately contribute to anti-proliferative effect, which is reversible and may influence therapeutic utility of metformin.

INSTRUMENT(S): Gas Chromatography MS - positive

PROVIDER: MTBLS7760 | MetaboLights | 2024-05-22

REPOSITORIES: MetaboLights

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Project description:Obesity-induced insulin resistance of the liver is characterised by increased gluconeogenesis, which contributes to elevated blood glucose levels in individuals with type 2 diabetes. Research into how fatty acids induce insulin resistance has commonly focused on the induction of insulin resistance. We hypothesise that by shifting focus to the reversal of an insulin resistant phenotype, novel insights can be made into the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered in parallel with restoration of palmitate-induced deregulation of glucose production using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0.075mM, 48h) with or without metformin (0.25mM) and sodium salicylate (2mM) in the final 24h of palmitate treatment, and effects on glucose production were determined. Microarray followed by gene set enrichment analysis was performed to investigate pathway regulation. A lipidomic analysis (HPLC-MS/MS) and measurement of secreted bile acids and cholesterol were performed. Reversal of palmitate-induced impairment of glucose production by metformin and sodium salicylate was characterised by down-regulated expression of metabolic pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis. Total levels of intracellular and secreted cholesterol and bile acids were not different between impaired and restored glucose production. Total intracellular levels of diacylgycerol, triacylglycerol and cholesterol esters increased with palmitate (impaired glucose production), however, these were not further altered with metformin and sodium salicylate (restored glucose production). Six individual lipid species containing 18:0 and 18:1 side-chains were reduced by metformin and sodium salicylate. Widespread lipid metabolism changes induced by the reversal of palmitate-induced deregulation of glucose production with metformin and sodium salicylate were identified. While cholesterol and bile acid levels remained unchanged, the flux through these pathways may in part explain these findings. The identification of lipid species containing 18:0 and 18:1 side chains being regulated alongside changes to glucose production may indicate potential mediators of glucose production and insulin resistance. Three-condition experiment, Vehicle, Palmitate (PA) and Palmitate (PA) + Metformin (Met) + Sodium Sailcylate (NaS) with biological replicates: 8 Vehicle, 20 PA and 20 PA+Met+NaS , independently grown and harvested. One replicate per array.

			Action	DRS
	HepG2_Rescue_Cell_MOX-TMS_14062022_03.D.zip	Other
	AcqData-CumulativeAuditTrail.xml	Xml
	Contents.xml	Xml
	Devices.xml	Xml
	MSTS.xml	Xml

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Analysis of glucose-independent metabolic pathways associated with anti-proliferative effect of metformin and their reversibility in liver cancer cells

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