of Tankyrase inhibition in ovarian cancer cell lines and Notch system crosstalk

TESONE MARTA; BOCCHICCHIO S; IRUSTA G

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2016

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 (XAV939: 1, 10, 20 and 50 µM), a Notch 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 together with an increase of total Axin when 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. At low concentrations (10, 100 µM), KGN cells proliferation increased while β-Catenin levels remained constant. On the contrary, when KGN cells were incubated in the presence of high concentrations of LiCl (5, 10 mM), cell proliferation decreased significantly as well as total Nf-κβ, while β-Catenin levels increased.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.