Annexin A1 is involved in the acquisition and maintenance of a stem cell-like/aggressive phenotype in prostate cancer cells with acquired resistance to zoledronic acid

// Valentina Bizzarro 1 , Raffaella Belvedere 1 , Maria Rita Milone 2 , Biagio Pucci 2 , Rita Lombardi 2 , Francesca Bruzzese 3 , Ada Popolo 1 , Luca Parente 1 , Alfredo Budillon 2, 3 , Antonello Petrella 1 1 Department of Pharmacy, University of Salerno, Fisciano (SA), Italy 2 Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale – IRCCS, Naples, Italy 3 Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale – IRCCS, Naples, Italy Correspondence to: Antonello Petrella, e-mail: apetrella@unisa.it Alfredo Budillon, e-mail: a.budillon@istitutotumori.na.it Keywords: annexin A1, prostate cancer, cell invasion, EMT, cancer stem cells Received: May 18, 2015      Accepted: July 16, 2015      Published: July 28, 2015 ABSTRACT In this study, we have characterized the role of annexin A1 (ANXA1) in the acquisition and maintenance of stem-like/aggressive features in prostate cancer (PCa) cells comparing zoledronic acid (ZA)-resistant DU145R80 with their parental DU145 cells. ANXA1 is over-expressed in DU145R80 cells and its down-regulation abolishes their resistance to ZA. Moreover, ANXA1 induces DU145 and DU145R80 invasiveness acting through formyl peptide receptors (FPRs). Also, ANXA1 knockdown is able to inhibit epithelial to mesenchymal transition (EMT) and to reduce focal adhesion kinase (FAK) and metalloproteases (MMP)-2/9 expression in PCa cells. DU145R80 show a cancer stem cell (CSC)-like signature with a high expression of CSC markers including CD44, CD133, NANOG, Snail, Oct4 and ALDH7A1 and CSC-related genes as STAT3. Interestingly, ANXA1 knockdown induces these cells to revert from a putative prostate CSC to a more differentiated phenotype resembling DU145 PCa cell signature. Similar results are obtained concerning some drug resistance-related genes such as ATP Binding Cassette G2 (ABCG2) and Lung Resistant Protein (LRP). Our study provides new insights on the role of ANXA1 protein in PCa onset and progression.