γ-secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets

Dorneburg, Carmen; Goß, Annika V.; Fischer, Matthias; Roels, Frederik; Barth, Thomas F.E.; Berthold, Frank; Kappler, Roland; Oswald, Franz; Siveke, Jens T.; Molenaar, Jan J.; Debatin, Klaus‐Michael; Beltinger, Christian

doi:10.18632/oncotarget.11715

Cited by 12 publications

(6 citation statements)

References 48 publications

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“…Thus, Notch activation is dependent on γ -secretase [ 30 ]. DAPT is a γ -secretase inhibitor and is commonly used to block Notch signaling [ 31 ]. Presenilin, a molecular target of DAPT, is an important component of the γ -secretase and critical for γ -secretase activity [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Notch1 Signaling Regulates the Th17/Treg Immune Imbalance in Patients with Psoriasis Vulgaris

Xue

Gao

et al. 2018

Mediators of Inflammation

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Purpose To evaluate the regulating effect of Notch1 signaling on Th17/Treg immune imbalance in psoriasis vulgaris (PV). Materials and Methods Notch1, Hes-1, RORγt, Foxp3, IL-17, and IL-10 mRNA expression, as well as Th17 and Treg cell percentages in peripheral CD4+ T cells, were detected by real-time quantitative RT-PCR and flow cytometry, and serum concentrations of IL-17 and IL-10 were detected by ELISA in 36 PV patients and 32 healthy controls. Additionally, CD4+ T cells from 12 PV patients were treated with γ-secretase inhibitor DAPT, and the above indexes were measured. Results PV patients presented distinct Th17/Treg immune imbalance and highly expressed Notch1 and Hes-1 mRNA levels, which were positively correlated with psoriasis area and severity index (PASI) and the ratios of Th17/Treg and RORγt/Foxp3. DAPT treatment resulted in the obvious downregulation of Th17 cell percentage in cocultured CD4+ T cells, RORγt and IL-17 mRNA levels, and IL-17 concentration in cell-free supernatant from cocultured CD4+ T cells of PV patients in a dose-dependent manner, while there was no significant influence on Treg cell percentage, Foxp3, and IL-10 expression, therefore leading to the recovery of Th17/Treg immune imbalance. Conclusion Notch1 signaling may contribute to the pathogenesis of PV by regulating Th17/Treg immune imbalance.

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Section: Discussionmentioning

confidence: 99%

Notch1 Signaling Regulates the Th17/Treg Immune Imbalance in Patients with Psoriasis Vulgaris

Xue

Gao

et al. 2018

Mediators of Inflammation

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show abstract

“…Notch signaling activation is dependent on γ-secretase [ 26 ]. DAPT is a γ-secretase inhibitor and commonly used to block Notch signaling, which can effectively interrupt presenilin, an important component of the γ-secretase and critical for γ-secretase activity, and finally result in the inhibition of active NICD release [ 27 , 28 ]. Evidences from in vitro study showed that both mouse and human RORγt expression can be significantly reduced by γ-secretase inhibitor treatment and/or Notch1-specific siRNA [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of γ-secretase inhibitor on Th17 cell differentiation and function of mouse psoriasis-like skin inflammation

Xue

et al. 2018

J Transl Med

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BackgroundTh17 cells and its effective cytokine IL-17A play an important role in the pathogenesis of abnormal immune responses in psoriasis. Notch1 signaling has been implicated in Th17 cell differentiation and function. In this study, our aim was to evaluate the possible inhibitory effect of Notch1 signaling inhibitor, γ-secretase inhibitor DAPT, on psoriatic Th17 cell differentiation and function in a mouse model of psoriasis-like skin inflammation.MethodsMouse psoriasis-like skin inflammation model was established by topical 5% imiquimod (IMQ) application, and experimental mice were divided into control group, IMQ-treated group and IM + DAPT-treated group. DAPT and the equivalent amount of Dimethyl sulfoxide was intraperitoneally injected in IMQ + DAPT-treated group and the other two experimental groups respectively. Skin tissues of the three experimental groups were acquired and stained with haematoxylin and eosin (HE). Splenic single-cells and serum were collected to detect the percentage of Th17 cells, the mRNA expression levels of Notch1 and its target gene Hes-1, Th17-specific transcription factor RORγt and its effective cytokines IL-17A, as well as IL-17A serum concentration. In addition, splenic CD4+ T cells from IMQ-treated mice were isolated and treated by DAPT to further measure the inhibitory effect of DAPT on the Th17 cell differentiation and IL-17A secretion in vitro.ResultsDAPT treatment alleviated the severity of IMQ-induced mouse psoriasis-like skin inflammation and decreased the scores of erythema, scaling and thickening. HE stain reveals obviously reduced epidermal hyperplasia and dermal inflammatory cells infiltration in IMQ + DAPT-treated mice. The increased expression of splenic Th17 cell percentage, along with Notch1, Hes-1, RORγt and IL-17A mRNA and IL-17A serum concentration in IMQ-treated mice were significantly decreased when experimental mice were treated by IMQ and DAPT combinedly. Data obtained from in vitro study in IMQ-treated mice also demonstrated that blocking Notch1 signaling by DAPT can result in a dose-dependent decrease of Th17 cell proportion, mRNA expression of Notch1, Hes-1, RORγt and IL-17A as well as IL-17A secretion in splenic CD4+ T cells.ConclusionThese data suggest that Notch1 inhibition by DAPT can effectively alleviate the severity of mouse psoriasis-like skin inflammation by regulating the differentiation and function of Th17 cells, indicating that DAPT might be a potential therapeutic candidate for the treatment of psoriatic inflammation.

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“…It is known that Notch pathway is also involved in various steps of vascular development in normal tissue and tumor angiogenesis; and tumor vascularity is associated with aggressive phenotypes including EMT (36,37). Recent evidence indicates that tumor cells with abnormal expression of Notch signaling triggers angiogenesis, and the targeting interruption, such as γ-secretase inhibitors, may provide effective measures (38). Taken together, Notch signaling as an initiator not only causes malignant aggressiveness but also co-activates with other pathways such as Ras, which might be critical for identifying potential therapeutic targets or modalities.…”

Section: Instructionmentioning

confidence: 99%

Novel transduction of nutrient stress to Notch pathway by RasGRP3 promotes malignant aggressiveness in human esophageal squamous cell carcinoma

Zhou

Zhu

et al. 2017

Oncology Reports

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In the process of enlarging of tumors, the dissolving tissue structures and remodeling endothelial cells for restoring gas exchange and nutritional support, further facilitate tumor cell invasion and metastasis. Activation of Ras plays a critical role in the development of esophageal squamous cell carcinoma (ESCC), but the underlying mechanisms remain poorly understood. We therefore investigated whether Ras guanyl-releasing protein 3 (RasGRP3), a Ras activator, could promote metastasis by inducing vascular regeneration and further epithelial-mesenchymal transition under nutrient stress (NS). In the present study, we explored that the accumulation of RasGRP3 regulated vascular endothelial growth factor-A production, co-stimulated Notch pathway with high expression of Notch intracellular domain (NICD) and Hes1. Moreover, ESCC cells under NS increased the expression of vimentin, Snail, Slug and MMP9 proteins; while inhibition of Notch activation by DAPT (a γ-secretase inhibitor) or RasGRP3-targeted RNA interference prevented from the effect. In conclusion, these findings provide a new insight into the upregulation of RasGRP3 involved in Notch pathway activation in the development of ESCC, especially under nutrient deprivation.

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γ-secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets

Cited by 12 publications

References 48 publications

Notch1 Signaling Regulates the Th17/Treg Immune Imbalance in Patients with Psoriasis Vulgaris

Notch1 Signaling Regulates the Th17/Treg Immune Imbalance in Patients with Psoriasis Vulgaris

Effect of γ-secretase inhibitor on Th17 cell differentiation and function of mouse psoriasis-like skin inflammation

Novel transduction of nutrient stress to Notch pathway by RasGRP3 promotes malignant aggressiveness in human esophageal squamous cell carcinoma

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