MiR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells

Marzia Pennati, Alessia Lopergolo, Valentina Profumo, Michelandrea De Cesare, Stefania Sbarra, Riccardo Valdagni, Nadia Zaffaroni, Paolo Gandellini, Marco Folini

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)579-597
Number of pages19
JournalBiochemical Pharmacology
Volume87
Issue number4
DOIs
Publication statusPublished - Feb 15 2014

Keywords

  • Autophagy
  • Cisplatin
  • LAMP3
  • miR-205
  • Prostate cancer
  • RAB27A

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

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