Unexplored gene PHKA1 interplays between glucose metabolism and breast cancer

Abstract

Cancer cells often undergo metabolic reprogramming, typically increasing their uptake and utilization of energy sources like glucose, fatty acids, lactate, glutamine, and pyruvate, while maintaining redox balance. Rather than relying on oxidative phosphorylation, cancer cells preferentially engage glycolysis to convert pyruvate into lactate. This metabolic reprogramming correlates with altered glucose metabolism and dysregulated insulin signalling. Diabetes is associated with increased risk of certain cancer types. Cancer database analysis of genes involved in glucose metabolism, insulin signalling and diabetes, identified an unexplored differentially expressed PHKA1 gene associated with poor patient survivability in breast cancer. Expression of the PHKA1 gene was found to be upregulated under an environment of high glucose and insulin in cancer cells. Silencing PHKA1 via siRNA led to marked decrease in proliferative, invasion, migratory, and stem-like properties of MDA-MB-231 and MCF-7 breast cancer cells. Experimental findings demonstrated reduced expression of mesenchymal markers (e.g., Vimentin, Zeb-1/2), cell cycle markers (e.g., CDK-2/4), and proliferative markers (e.g., Bcl-2 and Bcl-xl), while expression of epithelial markers (e.g., E-cadherin and Keratin-19) were enhanced in PHKA1 knockdown cells when compared to control. Performance of glycolysis stress and mito stress assay further demonstrated that siPHKA1 cells had diminished glycolytic activity alongside suppressed mitochondrial function. These findings highlight intricate relationship between metabolic dysregulation observed in diabetes, contributing to the progression of cancer. Collectively, these observations highlight PHKA1 as an oncogenic candidate with potential role in breast cancer. Comprehensive understanding of such metabolic alterations is critical to designing targeted therapeutic strategies aimed at mitigating breast cancer progression.