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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Autores principales:	Irusta, G., Maidana, C.P., Abramovich, D., De Zúñiga, I., Parborell, F., Tesone, M.
Formato:	JOUR
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:	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

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spelling	todo:paper_00063363_v89_n1_p_Irusta2023-10-03T14:04:59Z Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a foxl2-mutated granulosa tumor cell line (KGN) Irusta, G. Maidana, C.P. Abramovich, D. De Zúñiga, I. Parborell, F. Tesone, M. 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 apoptosis KGN cells Notch system PI3K/AKT signaling Amyloid Precursor Protein Secretases Apoptosis 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 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00063363_v89_n1_p_Irusta
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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 apoptosis KGN cells Notch system PI3K/AKT signaling Amyloid Precursor Protein Secretases Apoptosis 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
spellingShingle	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 apoptosis KGN cells Notch system PI3K/AKT signaling Amyloid Precursor Protein Secretases Apoptosis 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 Irusta, G. Maidana, C.P. Abramovich, D. De Zúñiga, I. Parborell, F. Tesone, M. Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a foxl2-mutated granulosa tumor cell line (KGN)
topic_facet	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 apoptosis KGN cells Notch system PI3K/AKT signaling Amyloid Precursor Protein Secretases Apoptosis 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
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 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.
format	JOUR
author	Irusta, G. Maidana, C.P. Abramovich, D. De Zúñiga, I. Parborell, F. Tesone, M.
author_facet	Irusta, G. Maidana, C.P. Abramovich, D. De Zúñiga, I. Parborell, F. Tesone, M.
author_sort	Irusta, G.
title	Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a foxl2-mutated granulosa tumor cell line (KGN)
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)
url	http://hdl.handle.net/20.500.12110/paper_00063363_v89_n1_p_Irusta
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Effects of an inhibitor of the gamma-secretase complex on proliferation and apoptotic parameters in a foxl2-mutated granulosa tumor cell line (KGN)

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