Gamma-Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and Wnt-Beta-Catenin Pathways in CD44+ Gastric Cancer Stem Cells. (3rd February 2017)

• Record Type: Journal Article
• Authors: Barat, Samarpita; Chen, Xi; Cuong Bui, Khac; Bozko, Przemyslaw; Götze, Julian; Christgen, Matthias; Krech, Till; Malek, Nisar P.; Plentz, Ruben R.
• Is Part Of: Stem cells translational medicine. Volume 6:Number 3(2017)
• Page Start: 819
• Page End: 829
• Publication Date: 2017-02-03
• Subjects: Cancer stem cells -- CD44 -- Gastric cancer -- Gamma-secretase inhibitor IX -- Notch -- wnt-beta-catenin; Stem cells -- Periodicals; Regenerative medicine -- Periodicals; Periodicals; 616.0277405
• DOI: 10.1002/sctm.16-0335
• Languages: English
• ISSNs: 2157-6564

Abstract

Abstract: Cancer stem cells (CSC) are associated with tumor resistance and are characterized in gastric cancer (GC). Studies have indicated that Notch and wnt-beta-catenin pathways are crucial for CSC development. Using CD44 + CSCs, we investigated the role of these pathways in GC carcinogenesis. We performed cell proliferation, wound healing, invasion, tumorsphere, and apoptosis assays. Immunoblot analysis of downstream signaling targets of Notch and wnt-beta-catenin were tested after gamma-secretase inhibitor IX (GSI) treatment. Immunohistochemistry, immunofluorescence, and Fluorescence activated cell sorting (FACS) were used to determine CD44 and Hairy enhancer of split-1 (Hes1) expression in human GC tissues. CD44 + CSCs were subcutaneously injected into NMR-nu/nu mice and treated with vehicle or GSI. GC patients with expression of CD44 and Hes1 showed overall reduced survival. CD44 + CSCs showed high expression of Hes1. GSI treatment showed effective inhibition of cell proliferation, migration, invasion, tumor sphere formation of CD44 + CSCs, and induced apoptosis. Importanly, Notch1 was found to be important in mediating a crosstalk between Notch and wnt-beta-catenin in CD44 + CSCs. Our study highlights a crosstalk between Notch and wnt-beta-catenin in gastric CD44 + CSCs. Expression of CD44 and Hes1 is associated with patient overall survival. GSI could be an alternative drug to treat GC.