Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a foxl2-mutated granulosa tumor cell line (KGN)

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 phospha...

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Detalles Bibliográficos
Publicado: 2013
Materias:
Apoptosis
Kgn cells
Notch system
Pi3K/akt signaling
caspase 8
Fas antigen
Fas ligand
gamma secretase inhibitor
Jagged1
nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase
Notch receptor
Notch1 receptor
Notch4 receptor
phosphatidylinositol 3 kinase
phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase
presenilin
progesterone
protein Bax
protein bcl 2
protein bcl xl
protein kinase B
transcription factor
transcription factor foxl2
unclassified drug
adult
apoptosis
article
cell death
cell growth
cell proliferation
cell survival
cell viability
complex formation
controlled study
extracellular matrix
female
gene mutation
granulosa cell tumor
human
human cell
infertility therapy
luteal cell
priority journal
protein cleavage
protein dephosphorylation
protein domain
protein expression
protein phosphorylation
protein protein interaction
signal transduction
steroidogenesis
tumor cell line
KGN cells
PI3K/AKT signaling
Amyloid Precursor Protein Secretases
Calcium-Binding Proteins
Cell Line, Tumor
Cell Proliferation
Dipeptides
Female
Forkhead Transcription Factors
Gonadal Steroid Hormones
Granulosa Cell Tumor
Humans
Intercellular Signaling Peptides and Proteins
Membrane Proteins
Mutation
Ovarian Neoplasms
Receptors, Notch
Acceso en línea:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00063363_v89_n1_p_Irusta
http://hdl.handle.net/20.500.12110/paper_00063363_v89_n1_p_Irusta
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
Descripción
Sumario: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 gammasecretase 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. © 2013 by the Society for the Study of Reproduction, Inc.

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