n-(n-(3-5-difluorophenacetyl)alanyl)phenylglycine-tert-butyl-ester and Endometrial-Neoplasms

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.

Topics: Amyloid Precursor Protein Secretases; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Cell Proliferation; Dipeptides; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Receptor, Notch1; RNA, Messenger; Signal Transduction; Transcription Factor HES-1

The aim of this study was to investigate the significance of the expression of Notch-related molecules in endometrial carcinoma.. The expression of Notch receptors (Notch1 and 3) and Notch ligands [Jagged (JAG) 1 and Delta-like (DLL) 4] was examined immunohistochemically in 37 normal and 76 malignant endometrial tissue samples. For each section, immunohistochemical staining was scored using a positivity index (PI, full score; 200). The effects of a Notch inhibitor, DAPT, on cell proliferation, invasion and motility were investigated using endometrial carcinoma cell lines. The PIs for Notch1 (mean±SD 90.4±15.3), Notch3 (95.6 ± 20.4), JAG1 (95.5±10.0) and DLL4 (88.2±9.6), were significantly higher in endometrial carcinoma than normal endometrium. The PI for Notch1 was associated significantly with advanced International Federation of Gynecologists & Obstetricians (FIGO) stage. In addition, patients with tumours showing high expression of both Notch1 and JAG1 had a poor prognosis compared with those having double-negative carcinomas (P=0.015). DAPT suppressed invasiveness of cells derived from the endometrial carcinoma cell line KLE.. The Notch1-JAG1 axis may enhance the invasive properties of endometrial carcinomas, which suggests the Notch pathway may be a promising target for the treatment of this malignancy.

Topics: Adaptor Proteins, Signal Transducing; Biomarkers, Tumor; Calcium-Binding Proteins; Carcinoma, Endometrioid; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dipeptides; Endometrial Neoplasms; Female; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Neoplasm Invasiveness; Prognosis; Receptor, Notch1; Receptor, Notch3; Receptors, Notch; Serrate-Jagged Proteins