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

Abstract

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 and Discussion: 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.

Identification and Validation of a Prognostic Signature Derived from the Cancer Stem Cells for Oral Squamous Cell Carcinoma

“…The expression of P4HA1 is markedly elevated in OSCC tissues, and heightened P4HA1 expression is linked to a more unfavorable prognosis [58]. Furthermore, a robust correlation exists between P4HA1 mRNA levels and various EMT and stem cell markers [59]. These investigations substantiate the pivotal involvement of the 6-GPS in the development of OSCC and propose that the genes identified in CSCMGs might serve as promising targets for laboratory-based experimentation.…”

Integrated single cell-RNA sequencing and Mendelian randomization for ischemic stroke and metabolic syndrome

“…P4HA1 is also associated with the glucose metabolism in pancreatic cancer cells (PDAC), where it can enhance the Warburg effect and tumor growth in PDAC. 19 P4HA1 is also a novel glycolysis-related gene in predicting the survival patients with colon adenocarcinoma. 20 TLR5 is originally found to increase in rat brains of focal ischemia models, and luteolin can downregulates TLR5-NFκB via reducing the expression of TLR5.…”

The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen

“…Prolyl-4-hydroxylation is a modification present in essentially all types of collagens and the drug could inhibit other enzymes that use α-ketoglutarate. Additionally, the consequences of P4h activity are not restricted to collagen; they impact the overall phenotype of the cell (e.g., stemness or Warburg effect) [ 95 ]. In this case, the treatment was locally applied via an intra-tracheal spray, initiated after injury induced by bleomycin, which improves the specificity in this complex scenario [ 94 ].…”