title: Functional redundancy of the Notch pathway in ovarian cancer cell lines.
abstract: Epithelial ovarian cancer is the most lethal gynecologic malignancy, despite advances in treatment. The most common histological type, high-grade ovarian serous carcinoma (OSC) is usually diagnosed at an advanced stage, and although these types of tumors frequently respond to surgery and platinum-based chemotherapy, they usually recur. Ovarian clear cell carcinoma (OCCC) is an unusual histological type, which is known to be intrinsically chemoresistant and is associated with poor prognosis in advanced stages. In recent years, genetic alterations and epigenetic modulation of signaling pathways have been reported in OSC and OCCC, including the overexpression of Notch pathway elements and histone deacetylases. Histone deacetylase inhibitors (HDACis), including vorinostat (suberoylanilide hydroxamic acid), alter the transcription of genes involved in cell growth, survival and apoptosis, and have become an attractive therapeutic approach. However, no previous work has addressed the effect of HDACis, and in particular vorinostat, on Notch signaling in ovarian cancer. Therefore, the present study aimed to investigate the modulation of the Notch pathway by vorinostat in ovarian cancer. Using immunofluorescence and quantitative polymerase chain reaction, the present results revealed that vorinostat activated the Notch pathway in OCCC and OSC cell lines, through different Notch ligands. In OCCC, the activation of the Notch pathway appeared to occur through Delta-like (Dll) ligands 1, 2 and 3, whereas in OSC Dll1 and Jagged 1 and 2 ligands were involved. The activation of the Notch pathway by vorinostat, in OCCC and OSC cell lines, culminated in the increased expression of the same downstream transcription factors, hairy enhancer of split (Hes) 1 and 5, andHes-related proteins 1 and 2. In conclusion, vorinostat modulates the expression of several downstream targets of the Notch pathway and independent Notch receptors and ligands that are expressed in OSC and OCCC. This upregulation of the Notch pathway may explain why vorinostat therapy fails in ovarian carcinoma treatment, as shown in certain clinical trials.
authors.affiliation: Chronic Diseases Research Center (CEDOC-FCM-UNL), NOVA Medical School, NOVA University of Lisbon, Lisbon 1169-056, Portugal; Molecular Pathobiology Research Unit, Portuguese Institute of Oncology Francisco Gentil (IPOLFG), Lisbon 1099-023, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Silva
authors.affiliation: Chronic Diseases Research Center (CEDOC-FCM-UNL), NOVA Medical School, NOVA University of Lisbon, Lisbon 1169-056, Portugal; Molecular Pathobiology Research Unit, Portuguese Institute of Oncology Francisco Gentil (IPOLFG), Lisbon 1099-023, Portugal; Department of Pathology, Portuguese Institute of Oncology Francisco Gentil (IPOLFG), Lisbon 1099-023, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Félix
authors.affiliation: Chronic Diseases Research Center (CEDOC-FCM-UNL), NOVA Medical School, NOVA University of Lisbon, Lisbon 1169-056, Portugal; Molecular Pathobiology Research Unit, Portuguese Institute of Oncology Francisco Gentil (IPOLFG), Lisbon 1099-023, Portugal.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Serpa
keywords: Notch pathway; ovarian cancer; vorinostat