RON and cisplatin resistance in ovarian cancer cell lines

RON (recepteur d'origine nantais) tyrosine kinase receptor has revealed its tumorigenic potential in recent studies. RON was reported to be overexpressed in 55% of primary ovarian carcinoma samples and furthermore its activation increases cell motility and invasiveness. In this study, we investigated the correlation between RON expression and chemoresistance in ovarian cancer cells. In A2780 cells, a model featured by high chemosensitivity to cisplatin, stable overexpression of RON was able to reduce sensitivity to this agent, while incubation with a blocking anti-RON antibody (ID1) increased the cisplatin-induced growth inhibition effect. Moreover, we observed an increased RON expression both at the mRNA and protein level in A2780 cells made resistant to doxorubicin and paclitaxel (A2780ADR and TC 1, respectively), two cell lines exhibiting a collateral resistance to cisplatin. OVCAR-3 cells, showing high levels of RON expression, also displayed inherent cisplatin resistance. The morphology observed in these resistant cells is consistent with a scattering phenotype and a RON-activated state. RON expression levels were monitored upon hypoxia. A 2.5-fold increase of RON expression was noticed in response to hypoxia in OVCAR-3 cells, in parallel with a decrease of E-cadherin mRNA. Altogether these results suggest an involvement of RON in the acquisition of cisplatin resistance and highlight the importance of this factor as a promising target for combination with cisplatin-based chemotherapy in ovarian cancer.