Targeting Notch as a therapeutic approach for human malignancies

Platonova, N.; Lesma, Elena; Basile, Andrea; Bignotto, Monica; Garavelli, S.; Palano, Maria Teresa; Moschini, A.; Neri, Antonino; Colombo, M.; Chiaramonte, Raffaella

doi:10.2174/1381612822666161006160524

Cited by 11 publications

(13 citation statements)

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“…Accumulating evidence shows that the Notch signaling pathway is overactive in lung, head and neck, pancreatic, bladder, and prostate cancer [ 18 , 19 , 23 – 26 ]. Furthermore, the high expression levels of Notch receptors and ligands have been associated with a poor prognosis in many malignant tumors [ 17 , 19 , 27 ]. In prostate cancer cells, activation of the Notch signaling pathway has been found to contribute to invasion and metastasis by EMT [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…The Notch signaling pathway is known to regulate a series of cellular processes, including cell proliferation, apoptosis, cell cycle, chemoresistance, migration, invasion, and stem cell maintenance [ 17 , 18 ]. Moreover, several studies have reported that Notch expression was upregulated in many human malignancies [ 17 , 19 – 21 ]. However, the function of Notch in the EMT biological processes of cervical cancer remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Cervical Cancer Cell Growth, Drug Resistance, and Epithelial-Mesenchymal Transition Are Suppressed by g-Secretase Inhibitor RO4929097

et al. 2018

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BackgroundThe Notch signaling pathway has been reported to play a pivotal role in tumorigenesis. Emerging evidence has demonstrated that the Notch signaling pathway regulates several cellular processes. The present study investigated the effect of the Notch signaling pathway on cell growth, invasiveness, and drug resistance, as well as epithelial-mesenchymal transition (EMT), of cervical cancer cells.Material/MethodsWe used quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis to measure the expression level of Notch2. CCK-8, clonality, wound healing, and Transwell assays were used to evaluate the effect of γ-secretase inhibitor (GSI) RO4929097 on cervical cancer cell lines HeLa and Caski. To explore the role of the Notch signaling pathway in EMT, the epithelial and mesenchymal markers were detected by qRT-PCR and Western blot after cervical cancer cell lines were treated with GSI RO4929097.ResultsThe expression of Notch2 was found to increase in cervical cancer cell lines compared with the normal immortalized human cervical epithelial cells. GSI RO4929097 was confirmed to inhibit the Notch signaling pathway and impaired the proliferation, drug resistance, migration, and invasion abilities of cervical cancer cells. The protein expression levels of the mesenchymal biomarkers Snail, Twist, and neural cadherin (N-cadherin) decreased; however, the expression of the epithelial biomarker epithelial cadherin (E-cadherin) increased in the cervical cancer cells treated with GSI RO4929097.ConclusionsNotch signaling pathway plays an important role in the development and progression of cervical cancer. Blockade of the Notch pathway using GSI RO4929097 inhibited cell growth and reduced chemoresistance, invasion, metastasis, and EMT in cervical cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cervical Cancer Cell Growth, Drug Resistance, and Epithelial-Mesenchymal Transition Are Suppressed by g-Secretase Inhibitor RO4929097

et al. 2018

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“…Upon ligand binding, two proteolytic cleavages release the intracellular Notch portion (ICN) which translocates to the nucleus and triggers the CSL (CBF1/Su(H)/Lag-1) transcription factor to transactivate the Notch target genes. Many of these genes are positive regulators of proliferation and survival and include c-Myc, Bcl2, HES1 [ 1 ], or are involved in the downstream regulation of anti-apoptotic/proliferative pathways such as AKT, NF-κB, Wnt and others [ 2 ]. Notch signaling has also been reported to play a crucial role in the regulation of stem cell and cancer stem cell renewal [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Hereditary diseases are determined by mutation in Notch-related genes resulting in reduced Notch signaling with consequent altered development such as Alagille syndrome, spondylocostal dysostosis [ 4 – 6 ] and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [ 7 ]. Oppositely, Notch-related cancers are more frequently associated to increased Notch activity, indicating an oncogenic role of Notch, although a tumor suppressor effect of Notch signaling has also been reported in a minor number of malignancies [ 2 ]. Notch signaling gain-of-function may be acquired by mutations in Notch receptors that, therefore, result constitutively activated independently from ligand engagement.…”

Section: Introductionmentioning

confidence: 99%

“…Notch signaling gain-of-function may be acquired by mutations in Notch receptors that, therefore, result constitutively activated independently from ligand engagement. This is the case of T-cell acute lymphoblastic leukemia (T-ALL) [ 8 ] and other tumors, including breast, ovarian, lung, prostate cancer [ 2 ]. On the other side, Notch signaling may be hyperactive although Notch activation still depends on ligand engagement.…”

Section: Introductionmentioning

confidence: 99%

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Identification of small molecules uncoupling the Notch::Jagged interaction through an integrated high-throughput screening

et al. 2017

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Notch signaling plays an important role in several cellular functions including growth, differentiation, cell fate determination and stemness. Increased Notch activity has been linked to several types of cancers. Activation of Notch signaling is triggered by the interaction of Notch receptors (Notch1-4) with 5 different ligands (Jagged1-2 and Dll1-3-4) expressed on the neighbouring cells. Currently, indirect approaches to inhibit Notch signalling are based on the inhibition of the key step of Notch activation catalyzed by the γ-Secretase and thereby affect several different γ-Secretase substrates; conversely direct strategies get advantage of antibody-based drugs. The evidence that Jagged-mediated Notch activation plays a key role in cancer cell biology and the interplay with the surrounding microenvironment prompted us to develop a strategy to directly inhibit Notch activation by uncoupling its interaction with the Jagged, using an unprecedented approach based on small molecules. We set-up a screening strategy based on: protein::protein docking of crystallographic structures of Notch1 with Jagged1; comparative modelling of the Notch2:Jagged2 complex, based on the Notch1::Jagged1 complex; in silico high-throughput screening directed to Notch2 interaction surface of a virtual chemical library containing a large variety of molecules commercially available. The predicted pharmacological activity of the selected compounds was validated in vitro by a gene reporter and a viability assay. This approach led to the successful identification of two candidates with different anti-proliferative potency and efficacy. This represents the first step towards the rational identification of candidate molecules for the development of entirely novel drugs directed to inhibit Notch signaling in cancer.

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Molecular mechanism of Notch signaling with special emphasis on microRNAs: Implications for glioma

Chen

et al. 2018

Journal Cellular Physiology

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Glioma is the most aggressive primary brain tumor and is notorious for resistance to chemoradiotherapy. Although its associated mechanisms are still not completely understood, Notch signaling, an evolutionarily conserved pathway, appears to be the key processes involved. Nevertheless, its mechanisms are sophisticated, due to a variety of targets and signal pathways, especially microRNA. MicroRNAs, which are small noncoding regulatory RNA molecules, have been proposed as one of the key mechanisms in glioma pathogenesis. Among the known glioma associated microRNA, microRNA-129, microRNA-34 family, and microRNA-326 have been shown to influence the progress of glioma through Notch signaling. Evidence also indicates that recurrence is due to development or persistence of the glioma stem-like cells and active angiogenesis, which are tightly regulated by a variety of factors, including Notch signaling. In this review, we summarize the recent progress regarding the functional roles of Notch signaling in glioma, including Notch ligand, microRNA, intracellular crosstalk, glioma stem-like cells and active angiogenesis and explore their clinical implications as diagnostic or prognostic biomarkers and molecular therapeutic targets for glioma.

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Targeting Notch as a therapeutic approach for human malignancies

Abstract: The provided evidence confirms the importance of Notch pathway in human malignancies indicating that a strong rationale exists for the development of a Notch-tailored therapy.

Cited by 11 publications

References 0 publications

Cervical Cancer Cell Growth, Drug Resistance, and Epithelial-Mesenchymal Transition Are Suppressed by g-Secretase Inhibitor RO4929097

Cervical Cancer Cell Growth, Drug Resistance, and Epithelial-Mesenchymal Transition Are Suppressed by g-Secretase Inhibitor RO4929097

Identification of small molecules uncoupling the Notch::Jagged interaction through an integrated high-throughput screening

Molecular mechanism of Notch signaling with special emphasis on microRNAs: Implications for glioma

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