Zhongguo aizheng zazhi (Nov 2021)
The effect of PAFR on cisplatin sensitivity in ovarian cancer cells and its mechanism
Abstract
Background and purpose: The current treatment of ovarian cancer is surgery and adjuvant platinum-based chemotherapy. However, relapse and drug resistance are common. We have demonstrated the platelet-activating factor receptor (PAFR) is highly expressed in epithelial ovarian cancer, promoting ovarian cancer cell proliferation and invasion. The objective was to explore the effect of PAFR expression on cisplatin (CDDP) in ovarian cancer cells to provide novel theoretical basis for ovarian cancer therapy. Methods: The upregulation of PAFR in CDDP-treated ovarian cancer cells was observed using Western blot and real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR). The role of nuclear factor Kappa-B (NF-κB)/p65 and hypoxia inducible factor- 1α (HIF-1α) in modulating PAFR expression was assessed using Western blot, siRNA and immunofluorescence. The effect of PAFR on CDDP sensitivity was observed using a pharmacological inhibitor and siRNA knockdown. Results: CDDP induced dose- and time- dependent upregulation of PAFR in two ovarian cancer cell lines (P ＜ 0.01). The downregulation of PAFR by CDDP correlated with the inhibitions of NF-κB and HIF-1α which were accumulated by CDDP in the nucleus. Inhibition of PAFR expression by PAFR specific small molecule antagonist WEB2086 or RNA interference could significantly improve the sensitivity of ovarian cancer cells to CDDP. The cell proliferation ability decreased significantly (P ＜ 0.01), while the apoptotic rate increased significantly (P ＜ 0.01). Increased expression of PAFR activated downstream AKT and ERK pathways in CDDP-treated cells. Conclusion: CDDP induces upregulation of PAFR by accumulating NF-κB and HIF-1α in the nucleus. PAFR inhibition may modulate the CDDP sensitivity in ovarian cancer cells, which is a novel and promising therapeutic target for sensitizing ovarian cancer cells to CDDP.
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