IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).
Autor/es:
GRISELDA IRUSTA; PAZOS CAMILA; ABRAMOVICH DALHIA; DE ZUÑIGA IGNACIO; PARBORELL FERNANDA; TESONE MARTA
Revista:
BIOLOGY OF REPRODUCTION
Editorial:
SOC STUDY REPRODUCTION
Referencias:
Lugar: Madison; Año: 2013 vol. 89 p. 9 - 15
ISSN:
0006-3363
Resumen:
Ovarian granulosa cell tumors (GCTs) represent 3%-5% of all ovarian
malignancies. Treatments have limited proven efficacy and biologically
targeted treatment is lacking. The aim of this study was to investigate
the role of Notch signaling in the proliferation, steroidogenesis,
apoptosis, and phosphatidylinositol 3-kinase (PI3K)/AKT pathway in a
FOXL2-mutated granulosa tumor cell line (KGN) representative of the
adult form of GCTs. When Notch signaling is initiated, the receptors
expose a cleavage site in the extracellular domain to the
metalloproteinase TACE and, following this cleavage, Notch undergoes
another cleavage mediated by the presenilin-gamma-secretase complex. To
achieve our goal, DAPT, an inhibitor of the gamma-secretase complex, was
used to investigate the role of the Notch system in parameters
associated with cell growth and death, using a human granulosa cell
tumor line (KGN) as an experimental model. We observed that JAGGED1,
DLL4, NOTCH1, and NOTCH4 were highly expressed in KGN cells as compared
to granulosa-lutein cells obtained from assisted reproductive techniques
patients. The proliferation and viability of KGN cells, as well as
progesterone and estradiol production, decreased in the presence of 20
μM DAPT. Apoptotic parameters like PARP and caspase 8 cleavages, BAX,
and BCLXs increased in KGN cells cultured with DAPT, whereas others such
as BCL2, BCLXl, FAS, and FAS ligand did not change. AKT phosphorylation
decreased and PTEN protein increased when Notch signaling was inhibited
in KGN cells. We conclude that the Notch system acts as a survival
pathway in KGN cells, and might be interacting with the PI3K/AKT
pathway.