Metformin increases PDH and suppresses HIF-1α under hypoxic conditions and induces cell death in oral squamous cell carcinoma

Abstract

BackgroundMetformin is a biguanide, belonging to the oral hypoglycemic agents and is a widely used in the treatment of type 2 diabetes. Evidence indicate that Metformin inhibits cell proliferation in several human cancers and inhibits the Warburg phenomenon in tumor cells.ResultsLow PDH levels were observed in OSCC, and Metformin promotes an increase in PDH levels in hypoxic conditions. Metformin also reduced HIF-1α mRNA and protein levels. Metformin demonstrated antiproliferative effects, inhibited migration, increased the number of apoptotic cells and increased the transcription of caspase 3.ObjectiveThe present study aims to explore the effects of Metformin in hypoxic conditions. Specifically, we focused on pyruvate dehydrogenase (PDH), (hypoxia-inducible factor 1α) HIF-1α levels and the oral squamous cell carcinoma (OSCC) cell phenotype. Additionally, we also investigated a theoretical consequence of Metformin treatment.MethodsPDH levels in patients with OSCC and oral dysplasia were evaluated. Metformin was administered in vitro to test the effect of Metformin under hypoxic conditions. The results were complemented by Bioinformatics analyses.ConclusionsIn conclusion, our current findings show that Metformin reduces HIF-1α gene expression and increases PDH expression. Metformin inhibits cell proliferation and migration in the OSCC cell line model. Additionally, Metformin enhances the number of apoptotic cells and caspase 3 levels. Interestingly enough, Metformin did not increase the mutant p53 levels under hypoxic conditions.

Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

“…Metformin ameliorated high fat diet‐induced HIF‐1α expression in mice and reduced obesity‐associated fibrosis and inflammation in adipose tissue . Metformin reduced levels of HIF‐1α mRNA and protein in hepatocellular and squamous cancer cells . Metformin reduced HIF‐1α protein levels by suppressing mitochondrial respiration thereby reducing cellular hypoxia .…”

“…127 Metformin reduced levels of HIF-1α mRNA and protein in hepatocellular and squamous cancer cells. 128 Metformin reduced HIF-1α protein levels by suppressing mitochondrial respiration thereby reducing cellular hypoxia. 129 Metformin improved diastolic function in diabetic rats.…”

The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth

“…Metformin reduces production of ROS (reactive oxygen species), oxidative stress and DNA damage through the inhibition of mitochondrial complex I [2, 35,54].…”

Metformin and Dicholoroacetate Combination Exert a Synergistic Effect on Cell Viability of Oral Squamous Cell Carcinoma

“…Recent studies have showed that the anti-diabetic drug, Metformin, inhibited the cell proliferation and induced cell death in several human cancers such as prostate cancer, [10] breast cancer, [11] and OSCC. [12] Moreover, metformin has a synergistic antitumor effect when used in combination with other well-known chemotherapeutic agents such as cisplatin, 5-fluorourasil, and paclitaxel. [13][14][15] Dichloroacetate is widely used in the treatment of lactic acidosis, inhibits pyruvate dehydrogenase kinase (PDK) via phosphorylation of pyruvate dehydrogenase.…”