Antiproliferative effects of γ-secretase inhibitor, a Notch signalling inhibitor, in multiple myeloma cells and its molecular mechanism of action

Hu, Jian; Zhu, Xiaoyan; Lu, Quanyi

doi:10.1177/0300060513485912

Cited by 7 publications

(7 citation statements)

References 38 publications

(58 reference statements)

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“…The role of GSI in inhibiting the growth of melanoma cell lines is consistent with the previous findings in other cancers ( 110 , 118 – 120 ). Notably, some research has shown an opposite outcome; the overexpression of NOTCH signaling can inhibit the growth of cancer cells through induction of cell cycle arrest ( 121 , 122 ).…”

Section: Discussionsupporting

confidence: 91%

FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma

et al. 2018

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Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor-β (TGF-β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF-β-induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno cytochemical analysis. Gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ-secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF-β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh-TGF-β. TGF-β-mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh-TGF-β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF-β-mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability.

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Section: Discussionsupporting

confidence: 91%

FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma

et al. 2018

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“…Therefore, we studied the cell cycle of tongue cancer cells, and our data indicate that the increased rate of apoptosis is related to cell cycle arrest. The cell cycle was blocked in G0/G1 phase after FLI-06 treatment, consistent with the effects of GSIs on other solid tumors, which also exhibit cell cycle arrest 36,37. Cancer stem cells may be related to the malignant characteristics of cancer, such as metastasis and recurrence 38,39.…”

Section: Discussionsupporting

confidence: 74%

<p>FLI-06 Intercepts Notch Signaling And Suppresses The Proliferation And Self-renewal Of Tongue Cancer Cells</p>

Gan

Lin

Xie

et al. 2019

OTT

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PurposeThe Notch signaling pathway plays an oncogenic role in tongue squamous cell carcinoma. The aim of this study was to inhibit the proliferation and self-renewal of tongue cancer cells by applying Notch signaling pathway inhibitor FLI-06 (Selleck, USA) and to lay a foundation for the clinically targeted treatment of tongue cancer for the future.MethodsThe mRNA expression level of Notch1 and the overall survival rate of patients with tongue cancer were examined by analyzing the TCGA database. Tongue cancer cells were treated with FLI-06. Cell proliferation, apoptosis, and stem cell self-renewal ability were tested in appropriate ways. A xenograft mouse model was established to observe tumor growth.ResultsFrom the TCGA data, we demonstrated that patients with high expression of Notch1 had a poor prognosis. We observed that the Notch signaling pathway inhibitor FLI-06 can restrain the activation of the Notch signaling pathway, decrease cell proliferation and induce cell apoptosis in vitro. The xenograft experiment indicated that intraperitoneal injection of FLI-06 inhibited tumor growth and increased cell apoptosis. FLI-06 suppressed both the mRNA and protein expression of Notch receptor and Notch targeted genes. We also observed that FLI-06 suppressed the proliferation of tongue cancer stem cells.ConclusionFLI-06 can block the proliferation and self-renewal of tongue cancer cells. It is inferred that this compound, which inhibits the Notch signaling pathway, may serve as a potential targeted drug for the treatment of tongue cancer in the clinic.

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“…29 GSIs possess potent antitumour activity to inhibit cell growth and induce cell apoptosis in many human cancers, such as breast cancer, hepatoma, myeloma, and pancreatic cancer, and some of them have already been tested in clinical trials. 30,31,32,33,34 Thus, to investigate the effect of Notch-1 inhibition on DTX-resistant LAD, we introduced a widely used GSI DAPT. Our data revealed that inhibition of Notch-1 by DAPT sensitizes resistant LAD cells to DTX treatment in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1

Huang

Chen

et al. 2016

Molecular Therapy - Nucleic Acids

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We previously demonstrated that expression of Notch-1 is associated with poor prognosis in lung adenocarcinoma (LAD) patients. The aim of this study is to reveal whether Notch-1 was associated with Taxanes-resistant LAD and, the underlying mechanisms. We collected 39 patients of advanced LAD treated with Taxanes and found that positive Notch-1 expression is closely related to LAD lymph node metastasis, recurrence and poorer prognosis, and Notch-1 acts as an independent poor prognostic factor in LAD by multivariate analysis with Cox regression model. Then, by using the Docetaxel (DTX)-resistant LAD cell lines that we established previously, we found that Notch-1 contributes to resistance of LAD cells to DTX in vitro, and inhibition of Notch-1 sensitizes LAD to DTX in vivo. We further demonstrated that Notch-1 mediates chemoresistance response and strengthens proliferation capacity in LAD cells partially through negative regulation of miR-451 by transcription factor AP-1. Moreover, we found that MDR-1 is a direct target of miR-451 and influences chemoresistance of LAD cells. Taken together, our data revealed a novel Notch-1/AP-1/miR-451/MDR-1 signaling axis, and suggested a new therapeutic strategy of combining DTX with Notch inhibitors to treat DTX-resistant LAD.

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Antiproliferative effects of γ-secretase inhibitor, a Notch signalling inhibitor, in multiple myeloma cells and its molecular mechanism of action

Cited by 7 publications

References 38 publications

FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma

FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma

<p>FLI-06 Intercepts Notch Signaling And Suppresses The Proliferation And Self-renewal Of Tongue Cancer Cells</p>

Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1

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