Phosphofructokinase 1 Platelet Isoform Enhances VEGF Expression in Part Through HIF-1α Up-regulation in Breast Cancer

Abstract

Background/Aim: Phosphofructokinase 1 platelet isoform (PFKP) catalyzes a rate-limiting reaction in glycolysis. It is highly expressed in several tumors, including breast cancer (BC). It can regulate tumor progression through metabolic reprogramming and gene transcription. In addition, overexpression of vascular endothelial growth factor (VEGF) is commonly observed in BC, which is associated with poor prognosis. However, whether PFKP regulates VEGF expression in BC remains unknown. Thus, the aim of this study was to investigate whether PFKP could regulate VEGF expression in BC. Materials and Methods: We designed an in vitro study to investigate the role of PFKP in VEGF expression and angiogenesis using several experiments, including shRNA-mediated PFKP knock-down, RNAi-resistant PFKP restoration, qPCR, immunoblotting, luciferase reporter assay and tube formation assay. The clinical relationship between PFKP and VEGF was analyzed using The Cancer Genome Atlas (TCGA) database. Results: PFKP expression was associated with VEGF expression in BC patients from the TCGA database. Importantly, PFKP played an essential role in the EGFR activation-induced VEGF expression in BC cells. Mechanistically, EGFR-phosphorylated PFKP Y64 played a critical role in AKT-mediated transcriptional expression of HIF-1α and subsequent VEGF transcription. Hence, PFKP expression played a role in human umbilical vein endothelial cells (HUVECs) tube formation by regulating VEGF expression in BC cells. Conclusion: These findings highlight a novel mechanism underlying the non-metabolic function of PFKP in VEGF expression in BC and provide a therapeutic potential of targeting PFKP in BC patients.