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Published on: November 28, 2019
Targeting Prolyl 3-hydroxylase 1 inhibits pancreatic cancer progression and macrophage immunity
Panzhu Bai1, Chengmin Liu1, Changying Fu2
1Department of Systems Biology, School of Life Sciences, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China.
Abstract:
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.
Insights
Prolyl 3-hydroxylase 1 (P3H1) drives pancreatic cancer progression by regulating Polo-like kinase 1 (PLK1) and β-catenin signaling. Inhibiting PLK1 enhances chemotherapy effectiveness against pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges due to limited therapeutic options and poor patient outcomes.
- Identifying key molecular pathways is essential for developing effective PDAC treatment strategies.
Purpose of the Study:
- To investigate the role of Prolyl 3-hydroxylase 1 (P3H1) in pancreatic ductal adenocarcinoma progression.
- To elucidate the downstream signaling pathways regulated by P3H1 in PDAC.
Main Methods:
- Transcriptome sequencing and proteomic analyses were employed to identify key molecular players.
- An engineered mouse model was utilized to study P3H1 function in vivo.
- Pharmacological inhibition of Polo-like kinase 1 (PLK1) was assessed for therapeutic efficacy.
Main Results:
- P3H1 was identified as a pivotal factor in PDAC progression.
- P3H1 regulates PDAC through Polo-like kinase 1 (PLK1) and subsequent β-catenin signaling.
- Restoring P3H1 or PLK1 expression in deficient cells normalized β-catenin signaling, enhanced proliferation, and promoted macrophage infiltration.
- PLK1 inhibition significantly improved chemotherapeutic response and reduced tumor burden in mice.
Conclusions:
- P3H1 plays a critical role in pancreatic ductal adenocarcinoma pathogenesis.
- Targeting the P3H1/PLK1/β-catenin axis represents a potential therapeutic strategy for PDAC.
- Inhibition of PLK1 enhances the efficacy of chemotherapy in PDAC treatment.
