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Targeted Therapy for Cancer Stem Cells
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik, Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu, Moorthy P. Ponnusamy
Notch signaling played a role in cell-cell communication and was found to be essential for cell proliferation and apoptosis during embryonic development. Several pathways such as nuclear factor-xB (NF-xB), HH, mammalian target of rapamycin (mTOR), Wnt, and epidermal growth factor have been shown to cross-talk with notch pathway, and thus, play significant functions in CSCs and tumor growth [69–71]. Therefore, Notch can be an attractive therapeutic target for CSCs treatment. Therapeutics aiming Notch signaling mainly consist of anti-Delta-like ligand 4 (DLL4) antibodies and g-secretase inhibitors. The main function of monoclonal antibodies against DLL4 is to block the binding of a ligand. Encticumab (REN421) is a DLL4 targeting antibody and has been used to treat advanced ovarian solid tumors overexpressing DLL4 [72]. Demcizumab is another anti-DLL4 antibody developed by OncoMed Pharmaceuticals and Celgene, and has completed the phase I clinical trial. In addition to inhibitors against DLL4, various g-secretase inhibitors such as RO4929097 and LY900009 have been undergoing phase I trial. RO4929097 suppresses Notch signaling genes, such as Hey1, Hey L and Hes1, thus blocking activation of self-renewal genes [10].
Alagille Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Genetically, ALGS is attributed to defects in the Notch signaling pathway, with mutation in the Jagged 1 (JAG1) gene on chromosome 20p12.2 accounting for a majority (∼96%) of cases (ALGS type 1), and mutation in the neurogenic locus notch homolog protein 2 (NOTCH2) gene on chromosome 1p12 being responsible for a small proportion (∼2%) (ALGS type 2, with prominent renal malformations). Both the JAG1 and NOTCH2 genes are components of the Notch signaling pathway [2].
Breast Cancer Stem Cells and Their Niche: Lethal Seeds in Lethal Soil
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Danuta Balicki, Brian Leyland-Jones, Max S. Wicha
The Notch signaling pathway plays an important role in regulating proliferation, survival, and differentiation of many cell types, including the regulation of self-renewal of adult stem cells and differentiation of progenitor cells along a particular lineage. These outcomes include increased survival or death, proliferation or growth arrest, and commitment to or blockage of differentiation. There are four mammalian Notch homologues, Notch 1 to 4, which interact with the DSL ligands: Delta, Delta-like, Jagged1, and Jagged2 in vertebrates (71).
Targeted next-generation DNA sequencing identifies Notch signaling pathway mutation as a predictor of radiation response
Published in International Journal of Radiation Biology, 2019
Seung Hyuck Jeon, Eui Kyu Chie, Yi-Jun Kim, Kyung-Hun Lee, Hyun-Seob Lee, Min Jung Kim, Seock-Ah Im, Jong-Il Kim, Tae-You Kim
The 39 KEGG pathways and the respective frequencies of mutation are shown in Table 3. The most commonly altered pathway was PI3K-Akt signaling pathway (67.3%, 37/55), followed by MAPK signaling pathway (63.6%, 35/55). On Fisher’s exact test, mutations in Notch signaling pathway were associated with radiation response (p = .002, adjusted p = .094). Distribution of primary cancer in the 7 patients with Notch signaling pathway mutations was diverse: hepatocellular carcinoma (n = 2), adenocarcinoma of colon (n = 1), invasive ductal carcinoma of breast (n = 1), undifferentiated pleomorphic sarcoma (n = 1), malignant peripheral nerve sheath tumor (n = 1), and squamous cell carcinoma of tongue (n = 1). Specifically, tumors with Notch signaling pathway mutations were more sensitive to radiation than the wild-type tumors. Among 55 patients, Notch signaling pathway mutations were found in 7 patients (12.7%) and 6 of them were responders. The logistic regression model of radiation response according to BED and Notch signaling pathway mutations is shown in Figure 2.
Osthole alleviates MPTP-induced Parkinson’s disease mice by suppressing Notch signaling pathway
Published in International Journal of Neuroscience, 2019
Yu Wang, Yong Zhou, Xiang Wang, Fei Zhen, Rui Chen, Deqin Geng, Ruiqin Yao
Notch signaling has been reported to play key roles in multiple processes, including individual developmental processes, cell proliferation, differentiation and cell fate decisions [30–32]. Notch 1, the central component of Notch signaling, is a transmembrane protein and is widespread in many tissues. Following ligand binding, Notch 1 is activated and regulates target genes, including Hes 1. Notch signaling was reported to be important to the pathological process of central nervous system disorder [33], and participated in aging process, such as Alzheimer's disease (AD) [34, 35]. In addition, osthole could improve neurological function through Notch signaling pathway in mice acute mechanical brain injury [18]. To explore the underlying mechanism of osthole alleviating MPTP-induced PD symptoms, we further investigated the effects of osthole on Notch signaling pathway. The results showed that Notch 1 and Hes 1 protein levels increased in LPS-induced BV-2 cells, and these alterations were attenuated by osthole treatment. Thus, we speculated that osthole alleviated MPTP-induced PD symptoms by suppressing Notch signaling pathway.
Rosuvastatin improves neurite extension in cortical neurons through the Notch 1/BDNF pathway
Published in Neurological Research, 2019
Weiliang He, Xiaochao Tian, Bilin Yuan, Bao Chu, Fan Gao, Hebo Wang
To further assess whether the Notch 1 pathway was involved in the effect of RSV on neurite outgrowth, we performed the following experiments. Firstly, Notch 1 expression was observed in the Tuj-1-positive neurons by immunostaining methods (Figure 3(a)). And we also found that Jagged 1, a ligand of Notch 1, and Notch 1 were colocated in the cells (Figure 3(b)). Secondly, Notch 1 and Hes 1 are the well-studied target genes of the Notch pathway [18]. So the levels of Notch1 and Hes1 genes were examined by qRT-PCT in different experiment groups. The results indicated that the Notch 1 and Hes 1 gene levels were significantly upregulated in the RSV group, but downregulated after co-treatment with DAPT. However, the Notch1 and Hes1 gene levels were not significantly different between the control group and the DAPT group (Figure 4(b,c)). Therefore, these results indicated that blockade of the Notch 1 pathway partially inhibited the RSV-mediated neurite extension in cortical neurons.