title: Effects of N-[N-(3, 5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) on cell proliferation and apoptosis in Ishikawa endometrial cancer cells.
abstract: Endometrial cancer is one of the most common gynecological malignancies in Japan, where the disease shows an increasing morbidity. However, surgical therapy remains the treatment of choice for endometrial cancers that tend to be insensitive to radiation therapy and chemotherapy. Therefore, novel therapeutic strategies are required. The Notch signaling pathway regulates embryogenesis and cellular development, but deregulated Notch signaling may contribute to tumorigenesis in several cancers. Moreover, γ-secretase inhibitors have been shown to be potent inhibitors of the Notch signaling pathway; they suppress cellular proliferation and induce apoptosis in several cancer cells. In the present study, we investigated the effect of N-[N-(3, 5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT, γ-secretase inhibitor) on the cell proliferation and apoptosis in Ishikawa endometrial cancer cells. Real-time PCR detected mRNA derived from NOTCH1 and HES1, which are target genes of the Notch signaling pathway, in Ishikawa endometrial cancer cells. After blocking Notch signaling, cellular proliferation decreased, accompanied by increased expression of p21 mRNA and decreased expression of the cyclin A protein. Furthermore, blockade of Notch signaling induced apoptosis. These results suggest that the Notch signaling pathway may be involved in cell proliferation through cell cycle regulation and apoptosis in Ishikawa endometrial cancer cells. Inhibition of the Notch signaling pathway by γ-secretase inhibitors is expected to be a potential target of novel therapeutic strategies for endometrial cancer.
authors.affiliation: Department of Chemical Technology, Graduate School of Science and Industrial Technology, Kurashiki University of Science and the Arts, Okayama, Japan. m-mori@sci.kusa.ac.jp
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mori
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yakushiji
authors.forename: Setsuyo
authors.initials: S
authors.lastname: Ohno
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Miyake
authors.forename: Takuya
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Hattori
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hongo
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nakaizumi
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ueda
authors.forename: Eiji
authors.initials: E
authors.lastname: Ohno
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology*; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D015398:Signal Transduction; D000072056:Transcription Factor HES-1
chemical_list: D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D004151:Dipeptides; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; C078493:HES1 protein, human