γ-secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity Journal Article

   

Authors:	Meng, R. D.; Shelton, C. C.; Li, Y. M.; Qin, L. X.; Notterman, D.; Paty, P. B.; Schwartz, G. K.
Article Title:	γ-secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity
Abstract:	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 γ-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 γ-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. ©2009 American Association for Cancer Research.
Keywords:	signal transduction; protein kinase b; controlled study; protein expression; unclassified drug; human cell; fluorouracil; cancer growth; drug potentiation; antineoplastic agents; protein domain; adenocarcinoma; complex formation; gene overexpression; metastasis; apoptosis; enzyme inhibition; 7 ethyl 10 hydroxycamptothecin; small interfering rna; colonic neoplasms; hct116 cells; transcription factor hes 1; receptor, notch1; enzyme activation; enzyme activity; chemosensitivity; cell line, tumor; phosphatidylinositol 3 kinase; irinotecan; sulfonamide; sulfonamides; colon cancer; cancer cell; proto-oncogene proteins c-akt; down regulation; upregulation; gene induction; protein subunit; oxaliplatin; organoplatinum compounds; ht29 cells; gamma secretase inhibitor; gsi 34; nicastrin; notch1 receptor; colon carcinogenesis; amyloid precursor protein secretases
Journal Title:	Cancer Research
Volume:	69
Issue:	2
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2009-01-15
Start Page:	573
End Page:	582
Language:	English
DOI:	10.1158/0008-5472.can-08-2088
PUBMED:	19147571
PROVIDER:	scopus
PMCID:	PMC3242515
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-58349091690&partnerID=40&md5=0e9780d3647e77820ad364e971b648ee
Notes:	--- - "Cited By (since 1996): 16" - "Export Date: 30 November 2010" - "CODEN: CNREA" - "Source: Scopus"

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