Title:Prolyl 4-hydroxylase P4HA1 Mediates the Interplay Between Glucose
Metabolism and Stemness in Pancreatic Cancer Cells
Volume: 18
Issue: 5
Author(s): Xiaopeng Cao*, Yi Cao, Hui Zhao, Pengfei Wang and Ziman Zhu
Affiliation:
- Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing, China
Keywords:
P4HA1, warburg effect, pancreatic cancer, cancer stemness, cancer stem cells, glucose metabolism.
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: 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 upregulated
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.
