PGK1 Promotes NSCLC Progression by Enhancing Aerobic Glycolysis and Activating AKT/ERK Signaling Pathway

Abstract Metabolic reprogramming, especially aerobic glycolysis is considered a hallmark of cancer, and is becoming a novel target for cancer therapy. Phosphoglycerate kinase I (PGK1) which is an important enzyme generating the first ATP in glycolysis pathway was already shown can promote some types of cancer development and progression, however, the role of PGK1 in lung cancer development is less reported. The aim of this study was to explore the mechanism of PGK1 in promoting non-small cell lung cancer (NSCLC) development and progression. Gene overexpression or silencing, scratch assay, Trans-well assay, western blot, immunohistochemistry, chromatin immunoprecipitation, real-time quantitative RT-PCR, MTT cell viability assay and mouse xenograft, glucose uptake, lactate secretion, ATP production and Extracellular Acidification Rate (ECAR) seahorse assay were performed to investigate the biological function and the underlying mechanism of PGK1 in NSCLC development. Our study found that PGK1 was high expressed in non-small cell lung cancer tissues, its expression is positive correlated with tumor grade and clinical stage and negative correlated with patients’ overall survival. Importantly, its expression was also associated with clinicopathological characteristics of lung cancer patients. Overexpression PGK1 could not only promote lung epithelial cell and tumor cell migration and proliferation in vitro, but also increase the tumor growth in vivo. Mechanically, PGK1 promotes NSCLC development and progression by activating AKT/ERK signaling pathway and altering aerobic glycolysis pathway. Meanwhile PGK1 was HIF1α downstream target gene and played an essential role in hypoxia-induced shift of glycolysis. In addition, the PGK1 expression was positive correlated with HIF1α expression in NSCLC tissues. Therefore, we concluded that PGK1 could be a biomarker for NSCLC diagnosis and outcome evaluation, and targeting PGK1 should be an innovative strategy for NSCLC therapy in the future.