Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a tumor granulosa cell line (KGN).

PAZOS CAMILA; ABRAMOVICH DALHIA; DE ZÚÑIGA IGNACIO; PARBORELL FERNANDA; TESONE MARTA; IRUSTA GRISELDA

Montreal

Congreso; 46th Annual Meeting of the Society for the Study of Reproduction; 2013

Ovarian granulosa cell tumors (GCTs) represent 3-5% of all ovarian malignancies and treatments have limited proven efficacy and biologically targeted treatment is lacking. The aim of this study was to investigate the role of Notch signaling on the proliferation, steroidogenesis, apoptosis, and PI3K/AKT pathway in a FOXL2-mutated tumor granulosa cell line (KGN), representative of the adult form of GCTs. For this purpose, an inhibitor of the g-secretase complex (DAPT) was used to investigate the role of Notch system in  parameters associated to cell growth and death using as an experimental model a human granulosa cell tumor line (KGN) .  We observed that JAGGED1, DLL4, NOTCH1 and NOTCH4 were highly expressed in tumor granulosa cells (KGN) compared to normal granulosa cells. The proliferation and viability of KGN cells decreased in the presence of DAPT 20µM and also progesterone and estradiol production. Apoptotic parameters like PARP cleavage, BAX, BCLXshort and caspase 8 cleavage increased in KGN cells in culture with DAPT, while others did not change (BCL2, BCLXlong, FAS and FASL). AKT phosphorylation decreased and PTEN protein increased when Notch signaling was inhibited in KGN cells. We conclude that Notch system acts as a survival pathway in a granulosa cell tumor line (KGN), and it might be interacting with the PI3K/AKT pathway.