Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells

Curry, Christine; Reed, Laura L; Golde, Todd E.; Miele, Lucio; Nickoloff, Brian J.; Foreman, Kimberly E.

doi:10.1038/sj.onc.1208783

Cited by 195 publications

(193 citation statements)

References 47 publications

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“…In this sense, higher expression of the Notch-like ligand, dlk, in MDS compared with myeloid leukemia cells has been detected by microarray analysis. 40 Notch activation has previously been associated to inhibition of apoptosis in normal endothelial 41 and T cells, 42 likewise in neoplastic cells including Kaposi's sarcoma, 43 glioma 44 and Hodgkin's lymphoma 45 cells. Conversely, Notch activation can induce apoptosis during the development of the retina 46 and the serotonin lineage 47 in Drosophila.…”

Section: Discussionmentioning

confidence: 99%

The notch pathway positively regulates programmed cell death during erythroid differentiation

et al. 2007

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Programmed cell death plays an important role in erythropoiesis under physiological and pathological conditions. In this study, we show that the Notch/RBPjj signaling pathway induces erythroid apoptosis in different hematopoietic tissues, including yolk sac and bone marrow as well as in murine erythroleukemia cells. In RBPjj À/À yolk sacs, erythroid cells have a decreased rate of cell death that results in increased number of Ter119 þ cells. A similar effect is observed when Notch activity is abrogated by incubation with the c-secretase inhibitors, DAPT or L685,458. We demonstrate that incubation with Jagged1-expressing cells has a proapoptotic effect in erythroid cells from adult bone marrow that is prevented by blocking Notch activity. Finally, we show that the sole expression of the activated Notch1 protein is sufficient to induce apoptosis in hexametilene-bisacetamide-differentiating murine erythroleukemia cells. Together these results demonstrate that Notch regulates erythroid homeostasis by inducing apoptosis.

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Section: Discussionmentioning

confidence: 99%

The notch pathway positively regulates programmed cell death during erythroid differentiation

et al. 2007

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“…Recently, they were widely used as a tool in anti-cancer studies. An increasing number of reports are revealing that GSIs offer a potential clinical application in cancer therapeutics, including treatment of glioblastomas [11][12][13][14][15][16] . A phase I trial of the γ-secretase inhibitor MK-0752 has been performed, and the results show that it is well-tolerated in children with recurrent CNS malignancies.…”

Section: Discussionmentioning

confidence: 99%

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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“…Endonuclease-mediated nucleosome excision manifesting as a DNA apoptosis ladder was also noted at 8 h and peaked at 24 h ( Figure 2d). As the inhibitory actions of the GSIs may not have been limited to only g-secretases, especially considering recent studies that revealed that the aldehyde group on the GSI-I peptide was able to covalently bind to and inhibit certain serine proteases (Curry et al, 2005), we had to exclude the possibility that the results we observed on the inhibition of Notch signaling were due to the inhibition of serine proteases and not g-secretases. To accomplish this, we performed experiments with GSI XIX, a noncovalent peptidomimetic inhibitor of g-secretases that is not able to bind serine proteases.…”

Section: Notch 3 Dependency Of Ibc Embolusmentioning

confidence: 99%

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

Xiao

Zou

et al. 2010

Oncogene

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Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells

Cited by 195 publications

References 47 publications

The notch pathway positively regulates programmed cell death during erythroid differentiation

The notch pathway positively regulates programmed cell death during erythroid differentiation

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

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

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