title: gamma-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 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.
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Laboratory of New Drug Development, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Meng
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Shelton
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.forename: Daniel
authors.initials: D
authors.lastname: Notterman
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C497761:NOTCH1 protein, human; D009944:Organoplatinum Compounds; D051881:Receptor, Notch1; D013449:Sulfonamides; D000077150:Oxaliplatin; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases