title: Gamma secretase inhibitor impairs epithelial-to-mesenchymal transition induced by TGF-β in ovarian tumor cell lines.
abstract: Ovarian cancer is characterized by being highly metastatic, a feature that represents the main cause of failure of the treatment. This study investigated the effects of γ-secretase inhibition on the TGF-β-induced epithelial-mesenchymal transition (EMT) process in ovarian cancer cell lines. SKOV3 cells incubated in the presence of TGF-β showed morphological and biochemical changes related to EMT, which were blocked by co-stimulation with TGF-β and the γ-secretase inhibitor DAPT. In SKOV3 and IGROV1 cells, the co-stimulation blocked the cadherin switch and the increase in the transcription factors Snail, Slug, Twist and Zeb1 induced by TGF-β. DAPT impaired the translocation of phospho-β-catenin to the inner cell compartment observed in TGF-β-treated cells, but was not able to block the induction at protein level induced by TGF-β. Moreover, the inhibitor blocked the increased cell migration and invasiveness ability of both cell lines induced by TGF-β. Notch target genes (Hes1 and Hey1) were induced by TGF-β, decreased by DAPT treatment and remained low in the presence of both stimuli. However, DAPT alone caused no effects on most of the parameters analyzed. These results demonstrate that the γ-secretase inhibitor used in this study exerted a blockade on TGF-β-induced EMT in ovarian cancer cells.
authors.affiliation: Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina. Electronic address: mariacamilapazos@gmail.com.
authors.forename: M C
authors.initials: MC
authors.lastname: Pazos
authors.affiliation: Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina. Electronic address: dnabramovich@gmail.com.
authors.forename: D
authors.initials: D
authors.lastname: Abramovich
authors.affiliation: Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina. Electronic address: andy_bechis@hotmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Bechis
authors.affiliation: Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina. Electronic address: paccialini@gmail.com.
authors.forename: P
authors.initials: P
authors.lastname: Accialini
authors.affiliation: Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina. Electronic address: fparborell@gmail.com.
authors.forename: F
authors.initials: F
authors.lastname: Parborell
authors.affiliation: Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina. Electronic address: martatesone.uba@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Tesone
authors.affiliation: Instituto de Biología y Medicina Experimental (IByME-CONICET), Buenos Aires, Argentina. Electronic address: irustag@gmail.com.
authors.forename: G
authors.initials: G
authors.lastname: Irusta
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D048430:Cell Shape / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000009:adverse effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D004151:Dipeptides; D004791:Enzyme Inhibitors; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D012333:RNA, Messenger; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D053829:Amyloid Precursor Protein Secretases
keywords: Cadherin switch; Epithelial-to-mesenchymal transition; Gamma secretase inhibitor; Metastasis; Ovarian cancer; TGF-β