title: Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation.
abstract: Epithelial ovarian carcinoma is characterized by high frequency of recurrence (70% of patients) and carboplatin resistance acquisition. Carcinoma-associated mesenchymal stem cells (CA-MSC) have been shown to induce ovarian cancer chemoresistance through trogocytosis. Here we examined CA-MSC properties to protect ovarian cancer cells from carboplatin-induced apoptosis. Apoptosis was determined by Propidium Iodide and Annexin-V-FITC labelling and poly-ADP-ribose polymerase cleavage analysis. We showed a significant increase of inhibitory concentration 50 and a 30% decrease of carboplatin-induced apoptosis in ovarian cancer cells incubated in the presence of CA-MSC-conditioned medium (CM). A molecular analysis of apoptosis signalling pathway in response to carboplatin revealed that the presence of CA-MSC CM induced a 30% decrease of effector caspases-3 and -7 activation and proteolysis activity. CA-MSC secretions promoted Akt and X-linked inhibitor of apoptosis protein (XIAP; caspase inhibitor from inhibitor of apoptosis protein (IAP) family) phosphorylation. XIAP depletion by siRNA strategy permitted to restore apoptosis in ovarian cancer cells stimulated by CA-MSC CM. The factors secreted by CA-MSC are able to confer chemoresistance to carboplatin in ovarian cancer cells through the inhibition of effector caspases activation and apoptosis blockade. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway and the phosphorylation of its downstream target XIAP underlined the implication of this signalling pathway in ovarian cancer chemoresistance. This study reveals the potentialities of targeting XIAP in ovarian cancer therapy.
authors.affiliation: 1] EA4553, Institut Claudius Regaud, Toulouse F-31052, France [2] University of Toulouse III, Toulouse F-31062, France.
authors.forename: M
authors.initials: M
authors.lastname: Castells
authors.forename: D
authors.initials: D
authors.lastname: Milhas
authors.forename: C
authors.initials: C
authors.lastname: Gandy
authors.forename: B
authors.initials: B
authors.lastname: Thibault
authors.forename: A
authors.initials: A
authors.lastname: Rafii
authors.forename: J-P
authors.initials: JP
authors.lastname: Delord
authors.forename: B
authors.initials: B
authors.lastname: Couderc
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D016190:Carboplatin; D053148:Caspase 3; D053179:Caspase 7; D002945:Cisplatin