title: Inhibition of gamma-secretase in Notch1 signaling pathway as a novel treatment for ovarian cancer.
abstract: Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. Most patients are not diagnosed until the cancer is at an advanced stage with poor prognosis. Notch1 signaling pathway plays an oncogenic role in EOC. There have been few studies on enzymatic activity of γ-secretase and the mechanism of how γ-secretase inhibitor works on cancer cell. Here, we show that Jagged1 and NICD were highly expressed in ovarian carcinoma. The expressions of Notch1, Jagged1 and NICD in Notch1 pathway did not correlate with outcome in ovarian cancer. The enzymatic activity of γ-secretase in ovarian cancer cell lines SKOV3, CAOV3 and ES2 is significantly higher than in normal ovarian epithelial cell line T29. DAPT (a γ-secretase inhibitor) reduced the enzymatic activity of γ-secretase, inhibited the proliferation, and increased the apoptosis in ovarian cancer cell lines. Hence, γ-secretase inhibitor may become a highly promising novel therapeutic strategy against ovarian cancer in the field of precision medicine.
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China.|Center for Cancer Immunology and Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Zhaoyi
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Wandong
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Medical Genetics, Capital Medical University, Beijing 100069, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Mengran
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Wen
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000072100:Jagged-1 Protein / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D016016:Proportional Hazards Models; D011480:Protease Inhibitors / Q000494:pharmacology*; D000072417:Protein Domains; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; D011480:Protease Inhibitors; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases
keywords: Jagged1; NICD; Notch; epithelial ovarian carcinoma; γ-secretase