Journal
BIOCHEMICAL PHARMACOLOGY
Volume 87, Issue 4, Pages 579-597Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.12.009
Keywords
Autophagy; Cisplatin; LAMP3; miR-205; Prostate cancer; RAB27A
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC, Special Program Innovative Tools for Cancer Risk Assessment and Early Diagnosis, 5X1000 project) [12162]
- AIRC [11542]
- Fondazione Italo Monzino
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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. (C) 2013 Elsevier Inc. All rights reserved.
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