Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).

Autores
Irusta, Griselda; Pazos Maidana, María Camila; Abramovich, Dalhia Nurit; de Zúñiga, Ignacio Javier; Parborell, Maria Fernanda Agustina; Tesone, Marta
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Irusta, Griselda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Pazos Maidana, María Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Abramovich, Dalhia Nurit. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: de Zúñiga, Ignacio Javier. Centro Médico PREGNA Medicina Reproductiva; Argentina
Fil: Parborell, Maria Fernanda Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Tesone, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Materia
KGN CELLS
NOTCH SYSTEM
PI3K/AKT SIGNALING
APOPTOSIS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
Atribución-NoComercial-CompartirIgual 2.5 Argentina (CC BY-NC-SA 2.5 AR)
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/2600
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/2600
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).Irusta, GriseldaPazos Maidana, María CamilaAbramovich, Dalhia Nuritde Zúñiga, Ignacio JavierParborell, Maria Fernanda AgustinaTesone, MartaKGN CELLSNOTCH SYSTEMPI3K/AKT SIGNALINGAPOPTOSIShttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Ovarian 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.Fil: Irusta, Griselda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Pazos Maidana, María Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Abramovich, Dalhia Nurit. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: de Zúñiga, Ignacio Javier. Centro Médico PREGNA Medicina Reproductiva; ArgentinaFil: Parborell, Maria Fernanda Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Tesone, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaSoc Study Reproduction2013-07-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/2600Irusta, Griselda; Pazos Maidana, María Camila; Abramovich, Dalhia Nurit; de Zúñiga, Ignacio Javier; Parborell, Maria Fernanda Agustina; et al.; Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).; Soc Study Reproduction; Biology Of Reproduction; 89; 1; 11-7-2013; 1-90006-33631529-7268enginfo:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/doi/10.1095/biolreprod.113.108100info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pubmed/23699387info:eu-repo/semantics/altIdentifier/url/http://www.biolreprod.org/content/89/1/9.longinfo:eu-repo/semantics/openAccessAtribución-NoComercial-CompartirIgual 2.5 Argentina (CC BY-NC-SA 2.5 AR)https://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-03-31T15:17:24Zoai:ri.conicet.gov.ar:11336/2600instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-03-31 15:17:25.031CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).
title Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).
spellingShingle Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).
Irusta, Griselda
KGN CELLS
NOTCH SYSTEM
PI3K/AKT SIGNALING
APOPTOSIS
title_short Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).
title_full Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).
title_fullStr Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).
title_full_unstemmed Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).
title_sort Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).
dc.creator.none.fl_str_mv Irusta, Griselda
Pazos Maidana, María Camila
Abramovich, Dalhia Nurit
de Zúñiga, Ignacio Javier
Parborell, Maria Fernanda Agustina
Tesone, Marta
author Irusta, Griselda
author_facet Irusta, Griselda
Pazos Maidana, María Camila
Abramovich, Dalhia Nurit
de Zúñiga, Ignacio Javier
Parborell, Maria Fernanda Agustina
Tesone, Marta
author_role author
author2 Pazos Maidana, María Camila
Abramovich, Dalhia Nurit
de Zúñiga, Ignacio Javier
Parborell, Maria Fernanda Agustina
Tesone, Marta
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv KGN CELLS
NOTCH SYSTEM
PI3K/AKT SIGNALING
APOPTOSIS
topic KGN CELLS
NOTCH SYSTEM
PI3K/AKT SIGNALING
APOPTOSIS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Irusta, Griselda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Pazos Maidana, María Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Abramovich, Dalhia Nurit. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: de Zúñiga, Ignacio Javier. Centro Médico PREGNA Medicina Reproductiva; Argentina
Fil: Parborell, Maria Fernanda Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Tesone, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
description 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.
publishDate 2013
dc.date.none.fl_str_mv 2013-07-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/2600
Irusta, Griselda; Pazos Maidana, María Camila; Abramovich, Dalhia Nurit; de Zúñiga, Ignacio Javier; Parborell, Maria Fernanda Agustina; et al.; Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).; Soc Study Reproduction; Biology Of Reproduction; 89; 1; 11-7-2013; 1-9
0006-3363
1529-7268
url http://hdl.handle.net/11336/2600
identifier_str_mv Irusta, Griselda; Pazos Maidana, María Camila; Abramovich, Dalhia Nurit; de Zúñiga, Ignacio Javier; Parborell, Maria Fernanda Agustina; et al.; Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN).; Soc Study Reproduction; Biology Of Reproduction; 89; 1; 11-7-2013; 1-9
0006-3363
1529-7268
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/
info:eu-repo/semantics/altIdentifier/doi/10.1095/biolreprod.113.108100
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pubmed/23699387
info:eu-repo/semantics/altIdentifier/url/http://www.biolreprod.org/content/89/1/9.long
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
Atribución-NoComercial-CompartirIgual 2.5 Argentina (CC BY-NC-SA 2.5 AR)
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv Atribución-NoComercial-CompartirIgual 2.5 Argentina (CC BY-NC-SA 2.5 AR)
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Soc Study Reproduction
publisher.none.fl_str_mv Soc Study Reproduction
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.822162

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