title: Notch3 overexpression as potential therapeutic target in advanced stage chemoresistant ovarian cancer.
abstract: This study examined the clinical significance of Notch3 expression and assessed its usefulness as a potential therapeutic target in chemoresistant ovarian cancer. Notch3 expression was assessed with immunohistochemical examination, and clinical variables were collected with a retrospective chart review. Notch3 siRNA or γ-secretase inhibitor was used to assess Notch3 function in ovarian cancer cell lines. Notch3 overexpression correlated with shorter progression-free/overall survival in patients with advanced stage (stage III, IV) ovarian carcinoma treated with platinum and taxane. Three of 5 patients showed increased Notch3 immunostaining in recurrent tumors compared with corresponding primary tumors. Notch3 overexpression was observed in both the cisplatin-resistant KFr13 and cisplatin/paclitaxel-resistant KFr13Tx cells. Inactivation of Notch3 by γ-secretase inhibitor or siRNA decreased cell proliferation and induced apoptosis in the KFr13 and KFr13Tx cells. Our findings suggest that Notch3 expression may be related to chemoresistance and that the Notch3 pathway may represent a novel therapeutic target for advanced stage chemoresistant ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Japan.
authors.forename: Mohammed Tanjimur
authors.initials: MT
authors.lastname: Rahman
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakayama
authors.forename: Munmun
authors.initials: M
authors.lastname: Rahman
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katagiri
authors.forename: Atsuko
authors.initials: A
authors.lastname: Katagiri
authors.forename: Tomoka
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Masako
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Kouji
authors.initials: K
authors.lastname: Iida
authors.forename: Satoru
authors.initials: S
authors.lastname: Nakayama
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Otsuki
authors.forename: Kohji
authors.initials: K
authors.lastname: Miyazaki
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D007564:Japan / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D017239:Paclitaxel / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D004791:Enzyme Inhibitors; C499374:NOTCH3 protein, human; D034741:RNA, Small Interfering; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D017239:Paclitaxel; D002945:Cisplatin