title: miR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells.
abstract: Compelling evidence suggests that epithelial-to-mesenchymal transition is involved in the resistance of human cancer cells to chemotherapy. We previously reported that the expression of miR-205, a miRNA down-regulated in prostate cancer, is further repressed in prostate cancer cells undergoing epithelial-to-mesenchymal transition, suggesting a possible involvement of the miRNA in the acquisition of the chemoresistant phenotype. In the present study, we show that miR-205 replacement in castration-resistant mesenchymal prostate cancer cells caused an enhancement of cisplatin cytotoxic activity in vitro and in vivo, as a consequence of autophagy impairment. Specifically, the constraints on the autophagic flux were associated to the miRNA-dependent down-regulation of the lysosome-associated proteins RAB27A and LAMP3. These findings suggest that miR-205-mediated impairment of the autophagic pathway may interfere with the detoxifying capabilities of prostate cancer cells in their attempt to cope with cisplatin-induced detrimental effects. Overall, our data indicate that (i) loss of miR-205 may indeed contribute to acquire mesenchymal tracts and concomitantly establish a permissive autophagic milieu that confers a chemotherapy resistant phenotype to prostate cancer cells, and (ii) strategies aimed at restoring miR-205 expression levels may represent a successful approach to overcome resistance of prostate cancer to platinum compounds.
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, 20133 Milano, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Pennati
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, 20133 Milano, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lopergolo
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, 20133 Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Profumo
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, 20133 Milano, Italy.
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, 20133 Milano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Sbarra
authors.affiliation: Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian 1, 20133 Milano, Italy; Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian 1, 20133 Milano, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Valdagni
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, 20133 Milano, Italy. Electronic address: nadia.zaffaroni@istitutotumori.mi.it.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, 20133 Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gandellini
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, 20133 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D003603:Cytotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D003603:Cytotoxins; D035683:MicroRNAs; C534425:MIR205, human
keywords: Autophagy; Cisplatin; LAMP3; Prostate cancer; RAB27A; miR-205