Effects of an Inhibitor of the Gamma-Secretase Complex on Proliferation and Apoptotic Parameters in a FOXL2-Mutated Granulosa Tumor Cell Line (KGN)1

Irusta, Griselda; Maidana, Camila Pazos; Abramovich, Dalhia; Zúñiga, Ignacio de; Parborell, Fernanda; Tesone, Marta

doi:10.1095/biolreprod.113.108100

Cited by 12 publications

(11 citation statements)

References 63 publications

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“…More recently, Wang et al (2011) have reported that in prostate cancer cells, the downregulation of NOTCH1 leads to the inhibition of cell growth mechanistically linked with the downregulation of AKT, suggesting that this protein is a downstream target of Notch1 signaling. In addition, in a previous work we have demonstrated that phosphorylation of AKT is repressed in a granulosa cell line (KGN) cultured with a Notch inhibitor (Irusta et al 2013). In this study, we showed that phosphorylation of AKT was inhibited in CL treated with DAPT and that this effect was reversed with coincubation with progesterone.…”

Section: Link Between Notch and Progesterone In CL Functionsupporting

confidence: 53%

“…In addition, different reports have demonstrated the interaction between the Notch signaling and PI3K/ AKT pathways in cancer cells (Meurette et al 2009, Wang et al 2011. In this context, we have recently demonstrated that Notch induces granulosa cell tumor proliferation, decreases apoptosis-mediated cell death, and might be interacting with the PI3K/AKT signaling pathway (Irusta et al 2013). Yet, the cellular mechanisms by which progesterone exerts its local effects and whether progesterone interacts with the Notch system in CL survival remain incompletely understood.…”

Section: Introductionmentioning

confidence: 90%

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A link between Notch and progesterone maintains the functionality of the rat corpus luteum

et al. 2015

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In this study, we investigated the interaction between the Notch pathway and progesterone to maintain the functionality of the corpus luteum (CL). When Notch signaling is activated, the g-secretase complex releases the active intracellular domains (NICD) of their receptors, which exert survival effects. We designed studies to analyze whether the in vitro inhibition of Notch affects progesterone production, steroidogenic regulators, apoptotic parameters, and signaling transduction pathways in the cultures of CL isolated from pregnant and superovulated rats. We detected a decrease in progesterone production when corpora lutea (CL) were incubated with N-(N-(3,5-difluorophenacetyl-L-alanyl))-S-phenylglycine t-butyl ester (DAPT), a g-secretase inhibitor. This effect could be in part due to the decrease detected in the CL protein levels of P450scc because STAR and 3b-hydroxysteroid dehydrogenase were not affected by Notch inhibition. Besides, the addition of aminoglutethimide to the CL culture medium decreased NICD of NOTCH1. We observed an increase in the expression of active CASPASE3 (CASP3) after inhibition by Notch, which was reversed by the presence of progesterone. The BAX:BCLX L ratio was increased in CL treated with DAPT and the presence of progesterone reversed this effect. In addition, phosphorylation of AKT was inhibited in CL treated with DAPT, but had no effect on ERK activation. To demonstrate that the action of DAPT is specifically related with the inhibition of Notch, CLs were incubated with DLL4 antibody and a decrease in progesterone production was detected. These results suggest the existence of a novel link between progesterone and the Notch signaling pathway to maintain the functionality of the CL.

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Section: Link Between Notch and Progesterone In CL Functionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 90%

A link between Notch and progesterone maintains the functionality of the rat corpus luteum

et al. 2015

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“…First, we detected cell growth and cell apoptosis in cells treated with DAPT only or in those treated with DAPT followed by t-AUCB. Because DAPT itself can also inhibit cell growth at certain concentrations and to avoid this effect, we applied DAPT at a low concentration of 2 μmol/L, which was demonstrated by others [19][20][21][22] and our current study have no significant effects on cell growth inhibition or cell apoptosis induction. Our results showed that with the pre-treatment of DAPT, cell growth inhibition in t-AUCB-treated U251 and U87 glioblastoma cells was strengthened significantly.…”

Section: Discussionmentioning

confidence: 56%

γ-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway

Wang

2014

Acta Pharmacol Sin

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Aim: -cyclohexyloxy]-benzoic acid (t-AUCB) is a soluble epoxide hydrolase inhibitor that suppresses glioblastoma cell growth in vitro. The aim of this study was to examine whether the γ-secretase inhibitor N- [N-(3,5-difluorophenacetyl)-lalanyl]-S-phenylglycine t-butyl ester (DAPT) could sensitize glioma cells to t-AUCB-induced apoptosis. Methods: Both U251 and U87 human glioblastoma cell lines were tested. Cell growth was assessed using the cell counting kit-8. Cell apoptosis was detected with caspase-3 activity assay kits and flow cytometry. The protein levels in the p38 MAPK/MAPKAPK2/Hsp27 pathway in the cells were analyzed using Western blots. Results: Pretreatment with DAPT (2 μmol/L) substantially potentiated the growth inhibition caused by t-AUCB (200 μmol/L) in U251 and U87 cells. Furthermore, pretreatment with DAPT markedly increased t-AUCB-induced apoptosis of U251 and U87 cells. T-AUCB alone did not significant affect caspase-3 activity in the cells, but t-AUCB plus DAPT pretreatment caused significant increase of caspase-3 activity. Furthermore, pretreatment with DAPT completely blocked t-AUCB-induced phosphorylation of p38 MAPK, MAPKAPK2 and Hsp27 in the cells. Conclusion: The γ-secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway, suggesting that the combination of t-AUCB and DAPT may be a potentially effective strategy for the treatment of glioblastoma.

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“…FOXO1/3 (forkhead box O1/3) also inhibited SMAD3 [ 12 ]. The interaction between Notch signaling and PI3K/AKT were also proved [ 13 ]. In the following sections, we will summarize the influence of different cell signaling network on GCT.…”

Section: Introductionmentioning

confidence: 99%

The molecular mechanism of ovarian granulosa cell tumors

et al. 2018

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Over these years, more and more sex cord-stromal tumors have been reported. Granulosa cell tumor (GCT) is a rare tumor in ovaries, accounts for 2% to 5% of ovarian cancers. The main different feature of GCTs from other ovarian cancers is that GCTs can lead to abnormally secreted hormones (estrogen, inhibin and Müllerian inhibiting substance). The GCT is divided into two categories according to the age of patients, namely AGCT (adult granulosa cell tumor) and JGCT (Juvenile granulosa cell tumor). AGCT patients accounts for 95%. Although the pathogenesis is not clear, FOXL2 (Forkhead box L2) mutation was considered as the most critical factor in AGCT development. The current treatment is dominated by surgery. Target therapy remains in the adjuvant therapy stage, such as hormone therapy. During these years, other pathogenic factors were also explored, such as PI3K/AKT (phosphatidylinositol-3-kinase; serine/threonine kinase), TGF-β (Transforming growth factor beta) signaling pathway, Notch signaling pathway, GATA4 and VEGF (vascular endothelial growth factor). These factors and signaling pathway play important roles in GCT cell proliferation, apoptosis, or angiogenesis. The purpose of this review is to summarize the possible pathogenic factors and signaling pathways, which may shed lights on developing potential therapeutic targets for GCT.

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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)1

Cited by 12 publications

References 63 publications

A link between Notch and progesterone maintains the functionality of the rat corpus luteum

A link between Notch and progesterone maintains the functionality of the rat corpus luteum

γ-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway

The molecular mechanism of ovarian granulosa cell tumors

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