Pancreatic ductal adenocarcinoma remains one of the most formidable challenges in oncology, with limited treatment options and a poor prognosis. Understanding the key pathways affecting cancer progression is crucial for the development of therapeutic strategies. Here, we reveal a pivotal role of Prolyl 3-hydroxylase 1 in pancreatic ductal adenocarcinoma using transcriptome sequencing, proteomic analyses and engineered mouse model. Mechanistically, our findings indicate that this effect is, at least in part, through the regulation of Polo-like kinase 1 and Polo-like kinase 1-mediated β-catenin signaling. Restoration of either Prolyl 3-hydroxylase 1 or Polo-like kinase 1 expression in Prolyl 3-hydroxylase 1-deficient cells reverses the defects of β-catenin signaling, facilitates tumor cell proliferation and elicits macrophage infiltration. In addition, pharmacological inhibition of Polo-like kinase 1 strongly increases the therapeutic efficacy of chemotherapeutic response against pancreatic ductal adenocarcinoma, alleviating tumor burden in mice. Our findings suggest a promising therapeutic strategy for treating pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer with poor prognosis and limited treatment options. This study identifies Prolyl 3- hydroxylase 1 (P3H1) as a critical regulator of PDAC progression through PLK1-β-catenin signaling, driving tumor-associated macrophage recruitment and tumor growth.
Bai et al. (Fri,) studied this question.