Prolyl 4-hydroxylase P4HA1 Mediates the Interplay Between Glucose Metabolism and Stemness in Pancreatic Cancer Cells

Introduction Cancer stem cells CSCs are profoundly implicated in tumor initiation and progression as well as drug resistance and tumor recurrence of many cancer types, especially pancreatic ductal adenocarcinoma PDAC. Previously, we revealed that prolyl 4-hydroxylase subunit alpha 1 P4HA1 enhances the Warburg effect and tumor growth in PDAC. However, the possible connection between P4HA1 and cancer stemness in PDAC remains obscure. In this study, P4HA1-dependent cancer stemness was studied by sphere-formation assay and detection of stemness markers. Methods Glycolytic capacity in cancer stem cells and their parental tumor cells was investigated by glucose uptake, lactate secretion, and expression of glycolytic genes. Glycolysis inhibitors were used to determine the link between cancer stemness and glycolysis. A subcutaneous xenograft model was generated to investigate P4HA1-induced stemness and glycolysis in vivo. Results We revealed that ectopic expression of P4HA1 increased the stemness of PDAC cells as evidenced by the increased proportion of CD133+ cells, elevated sphere-formation ability, and the up-regulated levels of cancer stemness-related proteins SOX2, OCT4, and NANOG. Blocking tumor glycolysis with 2-Deoxy-D-glucose 2-DG or a selective inhibitor of glucose transporter 1 STF-31 significantly reduced the stem properties of PDAC cells, suggesting that P4HA1-induced glycolysis was essential for the stem-like phenotype of PDAC cells. In addition, in vivo study reaffirmed a promotive effect of P4HA1 on tumor glycolysis and cancer stemness. Conclusion Collectively, our findings suggest that P4HA1 not only affects tumor metabolic reprogramming but also facilitates cancer stemness, which might be exploited as a vulnerable target for PDAC treatment.