Meng RD, Shelton CC, Li Y-M, Qin L-X, Notterman D, Paty PB, Schwartz GKγ-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res 69(2): 573-582

Department of Medicine, Division of Solid Tumor Oncology, Laboratory of New Drug Development, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cancer Research (Impact Factor: 9.33). 02/2009; 69(2):573-82. DOI: 10.1158/0008-5472.CAN-08-2088
Source: PubMed


Because Notch signaling is implicated in colon cancer tumorigenesis and protects cells from apoptosis by inducing prosurvival targets, it was hypothesized that inhibition of Notch signaling with gamma-secretase inhibitors (GSI) may enhance the chemosensitivity of colon cancer cells. We first show that the Notch-1 receptor, as well as its downstream target Hes-1, is up-regulated with colon cancer progression, similar to other genes involved in chemoresistance. We then report that chemotherapy induces Notch-1, as oxaliplatin, 5-fluorouracil (5-FU), or SN-38 (the active metabolite of irinotecan) induced Notch-1 intracellular domain (NICD) protein and activated Hes-1. Induction of NICD by oxaliplatin was caused by an increase in the activity and expression of gamma-secretase complex, as suppression of the protein subunit nicastrin with small interfering RNA (siRNA) prevented NICD induction after oxaliplatin. Subsequent inhibition of Notch-1 signaling with a sulfonamide GSI (GSI34) prevented the induction of NICD by chemotherapy and blunted Hes-1 activation. Blocking the activation of Notch signaling with GSI34 sensitized cells to chemotherapy and was synergistic with oxaliplatin, 5-FU, and SN-38. This chemosensitization was mediated by Notch-1, as inhibition of Notch-1 with siRNA enhanced chemosensitivity whereas overexpression of NICD increased chemoresistance. Down-regulation of Notch signaling also prevented the induction of prosurvival pathways, most notably phosphoinositide kinase-3/Akt, after oxaliplatin. In summary, colon cancer cells may up-regulate Notch-1 as a protective mechanism in response to chemotherapy. Therefore, combining GSIs with chemotherapy may represent a novel approach for treating metastatic colon cancers by mitigating the development of chemoresistance.

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    • "gov) (Richter et al. 2014, Lee et al. 2015, LoConte et al. 2015, Messersmith et al. 2015). Moreover, inhibiting Notch signaling (i.e., by pretreatment) has been shown to sensitize tumors to platinum compounds or other cytotoxic drugs, such as gemcitabine (Meng et al. 2009, Wang et al. 2010, McAuliffe et al. 2012). Finally, because the Notch ligand JAG1 is overexpressed in many cancers and plays an important role in tumor biology (Steg et al. 2011), targeting JAG1 directly may represent a promising therapeutic tool (Dai et al. 2014, Li et al. 2014). "
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    ABSTRACT: Previous SNP array analyses revealed genomic alterations of the Notch pathway as the most frequent abnormality in adrenocortical tumors (ACT). Aim of the study was to evaluate the expression of components of Notch signaling in ACT and to correlate them with clinical outcome. The mRNA expression of JAG1, NOTCH1, and selected target genes of Notch1 (HES1, HES5, HEY2) was evaluated in 80 fresh-frozen samples (28 normal adrenal glands=NAG, 24 adenomas=ACA, 28 carcinomas=ACC) by qRT-PCR. Immunohistochemistry was performed in 221 tissues on paraffin slides (16 NAG, 27 ACA, 178 ACC) for Jagged1, activated NOTCH1 (aNOTCH1) and HEY2. An independent ACC validation cohort (n=77) was also investigated. HEY2 mRNA expression was higher in ACC than in ACA (P<0.05). Protein expression of all factors was high (H-score 2-3) in a larger proportion of ACCs than ACAs and NAG (Jagged1 in 27%, 15% and 10%; aNOTCH1 in 13%, 8% and none; HEY2 in 66%, 61% and 33%, respectively, all P<0.001). High Jagged1 expression was associated with earlier tumor stages and lower number of metastases in ACC (both P=0.08), and impacted favorably on overall and progression free survival (131 vs 30 months, HR=0.45, and 37 vs 9 months, HR=0.51, both P<0.005). This impact on overall survival was confirmed in the validation cohort. No such association was observed for aNOTCH1 or HEY2. In conclusion, different components of the Notch1 signaling pathway are overexpressed in ACC, suggesting a role in malignant transformation. However, Jagged1 is overexpressed in a subgroup of ACCs with a better clinical outcome.
    Endocrine Related Cancer 05/2015; 22(4). DOI:10.1530/ERC-15-0163 · 4.81 Impact Factor
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    • "In human beings, Notch signaling was shown to be strongly activated in primary human colorectal cancers, and has an important role in cancer initiation and progression through the regulation of the main cellular functions associated with tumorigenesis, such as apoptosis, proliferation, angiogenesis, and cell migration. Microarray analysis discovered that the expression levels of Notch1, and its target Hes1, increased with increasing tumor grade (139). In situ hybridization on 130 colorectal cancer samples found that Notch signaling is constantly activated as measured by Hes1 expression (86). "
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    ABSTRACT: The Notch pathway is increasingly attracting attention as a source of therapeutic targets for cancer. Ligand-induced Notch signaling has been implicated in various aspects of cancer biology; as a consequence, pan-Notch inhibitors and therapeutic antibodies targeting one or more of the Notch receptors have been investigated for cancer therapy. Alternatively, Notch ligands provide attractive options for therapy in cancer treatment due to their more restricted expression and better-defined functions, as well as their low rate of mutations in cancer. One of the Notch ligands, Jagged1 (JAG1), is overexpressed in many cancer types, and plays an important role in several aspects of tumor biology. In fact, JAG1-stimulated Notch activation is directly implicated in tumor growth through maintaining cancer stem cell populations, promoting cell survival, inhibiting apoptosis, and driving cell proliferation and metastasis. In addition, JAG1 can indirectly affect cancer by influencing tumor microenvironment components such as tumor vasculature and immune cell infiltration. This article gives an overview of JAG1 and its role in tumor biology, and its potential as a therapeutic target.
    Frontiers in Oncology 09/2014; 4:254. DOI:10.3389/fonc.2014.00254
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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 glioblastomas11,12,13,14,15,16. 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. "
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    ABSTRACT: Aim: Trans-4-[4-(3-adamantan-1-yl-ureido)-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)-l-alanyl]-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.
    Acta Pharmacologica Sinica 05/2014; 35(6). DOI:10.1038/aps.2013.195 · 2.91 Impact Factor
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