CONICET | Buscador de Institutos y Recursos Humanos

Notch and Wnt/β-catenin are highly conserved pathways which regulate proliferation, apoptosis and differentiation. While Notch system has widely been demonstrated to be involved in ovarian cancer, Wnt/β-catenin pathway has been poorly studied in these tumors. Besides, there is little evidence that suggests a crosstalk between them. We analyzed the effect of inhibiting these two pathways and their interaction in ovarian cancer cell lines. Two human ovarian tumor cell lines, a human granulosa-like tumor cell line (KGN) and a human ovarian adenocarcinoma cell line (IGROV-1) were incubated in the presence of a Wnt inhibitor (the tankyrase inhibitor XAV939: 1, 10, 20 and 50 µM), a Notch inhibitor (the gamma secretase inhibitor DAPT: 15, 20 µM) or both. We evaluated the involvement of Wnt/β-catenin pathway and a crosstalk with Notch system in cellular proliferation.Our results show a significant decrease in proliferation when IGROV-1 cells were incubated in the presence of XAV939 (10, 20 and 50 µM) or DAPT (15, 20 µM). There was also a significant decrease in β-Catenin and Cyclin D1 levels and in addition a significant increase of total Axin when IGROV-1 cells were treated with XAV939. KGN cells also showed a significant decrease in proliferation after incubation with XAV939 (50µM). Most importantly, when IGROV-1 and KGN cells were incubated in the presence of both inhibitors, there was a synergistic decrease in proliferation suggesting a novel crosstalk between these pathways in ovarian cancer cell lines. We also tested a Wnt/β-Catenin pathway activator: LiCl. The proliferation results using this compound suggest a biphasic effect related to the Nf-kβ action.In conclusion, we demonstrate a clear involvement of Wnt/β-catenin pathway in ovarian tumor cell proliferation and suggest an interaction between this pathway and Notch system.