The expression of platelet-activating factor receptor modulates the cisplatin sensitivity of ovarian cancer cells: a novel target for combination therapy.

BACKGROUND: Ovarian cancer has the highest mortality rate of the gynaecological cancers. Although cisplatin (CDDP) is an effective treatment for ovarian cancer, recurrence is frequent and leads to death. The objective was to explore the role and possible mechanisms of platelet-activating factor receptor (PAFR) signalling in CDDP-treated ovarian cancer cells.

METHODS: The upregulation of PAFR in CDDP-treated ovarian cancer cells was observed using realtime PCR and Western blot. The potential role of PAFR in modulating the CDDP sensitivity was assessed using a pharmacological inhibitor and siRNA knockdown. The PAFR-activated signalling pathways involved in cell responses to CDDP were assessed.

RESULTS: Cisplatin induced increased PAFR expression in two ovarian cancer cell lines. The upregulation of PAFR by CDDP correlated with the time-dependent accumulation of NF-κB and HIF-1α in the nucleus. The inhibition of PAFR sensitised the ovarian cancer cells to CDDP. The PI3K and ERK pathways lie downstream of activated PAFR in CDDP-treated cells and their inhibition enhanced CDDP sensitivity. Finally, co-treatment with a PAFR antagonist (Ginkgolide B) and CDDP markedly reduced tumour growth in an in vivo model of ovarian cancer.

CONCLUSIONS: Together, these findings suggest that PAFR is a novel and promising therapeutic target for sensitising ovarian cancer cells to CDDP.