Effects of N-[N-(3, 5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT) on cell proliferation and apoptosis in Ishikawa endometrial cancer cells

Mori, Michihiro; Miyamoto, Tomoyuki; Yakushiji, Hiromasa; Ohno, Setsuyo; Miyake, Yasuyuki; Sakaguchi, Takuya; Hattori, Manabu; Hongo, Atsushi; Nakaizumi, Akihiko; Ueda, Masatsugu; Ohno, Eiji

doi:10.1007/s13577-011-0038-8

Cited by 16 publications

(13 citation statements)

References 21 publications

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“…Gamma-secretase inhibitors have been shown to be potent inhibitors of the Notch signaling pathway. In particular, DAPT has been widely used to perform studies in different types of tumor cell lines such as endometrial cells, breast cancer cells, gastric cancer cells, and some animal models [39][40][41]. In this study, the inhibition of the Notch system decreased proliferation and viability of the granulosa tumor cell line.…”

Section: Discussionmentioning

confidence: 90%

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

Maidana

Abramovich

et al. 2013

Biology of Reproduction

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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.

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Section: Discussionmentioning

confidence: 90%

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

Maidana

Abramovich

et al. 2013

Biology of Reproduction

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show abstract

“…Upon activation, Notch is cleaved, releasing the intracellular domain of Notch (ICN) through a cascade of proteolytic cleavages by the metalloprotease tumor necrosis factor-α converting enzyme and the γ-secretase complex (26,27). Therefore, inhibiting the γ-secretase function is likely to prevent the cleavage of the Notch receptor and block the Notch signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Gastric cancer cell growth and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT

Yang

Liu

et al. 2014

Oncology Letters

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Abstract. The Notch signaling pathway may be important in the development and progression of several malignancies. However, the functions of Notch signaling in epithelial-mesenchymal transition (EMT) remain largely unknown. The aim of the present study was to delineate Notch1 expression in gastric cancer (GC) and its function in GC EMT. Using quantitative polymerase chain reaction and western blot analysis, the expression of Notch1 was found to increase in GC cell lines compared with the normal gastric mucosa cell line. In addition, Notch1 expression was found to be downregulated in the non-metastatic-derived GC cell line compared with the metastatic-derived cell line. Furthermore, Notch1 expression was significantly increased in the tumor tissues compared with the adjacent normal mucosa tissues, as well as in patients with metastases than in patients without metastases. To explore the role of the Notch1 signaling pathway in EMT, the GC cell lines, AGS and MKN45, were treated with γ-secretase inhibitor DAPT. Using MTT, Transwell and clonality assays, DAPT was found to inhibit the expression of the Notch1 downstream target, Hes1, and impair the ability of the GC cell lines to migrate, invade and proliferate. The protein levels of the mesenchymal markers, vimentin, neural cadherin and Snail, were decreased; however, the expression of the epithelial marker, epithelial cadherin, was increased in the GC cell lines

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“…In hepatocellular carcinoma cells, the up-regulation of cyclinA has been observed after the activation of Wnt/β-catenin signaling pathway [24]. Down-regulation of Notch signaling pathway decreases the expression of cyclinA in Ishikawa endometrial cancer cells [25] and pancreatic cancer cells [26]. Inhibition of Wnt signaling pathway stimulates apoptosis with the increase of caspase-3 in adrenocortical cancer cell line H295R [27] and lung cancer line cells [28].…”

Section: Discussionmentioning

confidence: 99%

The Roles of Notch3 on the Cell Proliferation and Apoptosis Induced by CHIR99021 in NSCLC Cell Lines: A Functional Link between Wnt and Notch Signaling Pathways

Zhang

et al. 2013

PLoS ONE

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Wnt and Notch signaling pathways both play essential roles and interact closely in development and carcinogenesis, but their interaction in non-small-cell lung cancer (NSCLC) is poorly unknown. Here we investigated the effects of CHIR99021, a Wnt signaling agonist, or Notch3-shRNA, or the combined application of CHIR99021 and Notch3-shRNA on cell proliferation and apoptosis, as well as the expressions of Notch3, its downstream genes, cyclinA and caspase-3. Our results showed that CHIR99021 up-regulated the expression of Notch3 protein and HES1 and HEYL mRNA. CHIR99021 promoted cell proliferation and the expression of cyclinA, which were inhibited by Notch3-shRNA in these three cell lines. Moreover, Notch3-shRNA significantly attenuated the positive effects of CHIR99021 on cell proliferation and cyclinA in H460 and H157. As for apoptosis, Notch3-shRNA induced cell apoptosis and increased the expression of caspase-3, whereas CHIR99021 showed the different effects in these three cell lines. The inhibitory effect of CHIR99021 on apoptosis was significantly weakened by Notch3-shRNA only in H460. Overall, although the effects of CHIR99021 and the combined application of CHIR99021 and Notch3-shRNA on the cell proliferation and apoptosis aren’t completely similar in the three cell lines, our findings still indicate that Notch3 signaling can be activated by canonical Wnt signaling and a functional link between Wnt and Notch signaling pathways exists in NSCLC, at least, which partially is associated with their regulations on the expressions of cyclinA and caspase-3.

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Effects of N-[N-(3, 5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT) on cell proliferation and apoptosis in Ishikawa endometrial cancer cells

Cited by 16 publications

References 21 publications

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

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

Gastric cancer cell growth and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT

The Roles of Notch3 on the Cell Proliferation and Apoptosis Induced by CHIR99021 in NSCLC Cell Lines: A Functional Link between Wnt and Notch Signaling Pathways

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