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 language | English |
|---|---|
| Pages (from-to) | 579-597 |
| Number of pages | 19 |
| Journal | Biochemical Pharmacology |
| Volume | 87 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Feb 15 2014 |
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Keywords
- Autophagy
- Cisplatin
- LAMP3
- miR-205
- Prostate cancer
- RAB27A
ASJC Scopus subject areas
- Pharmacology
- Biochemistry
Cite this
MiR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells. / Pennati, Marzia; Lopergolo, Alessia; Profumo, Valentina; De Cesare, Michelandrea; Sbarra, Stefania; Valdagni, Riccardo; Zaffaroni, Nadia; Gandellini, Paolo; Folini, Marco.
In: Biochemical Pharmacology, Vol. 87, No. 4, 15.02.2014, p. 579-597.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MiR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells
AU - Pennati, Marzia
AU - Lopergolo, Alessia
AU - Profumo, Valentina
AU - De Cesare, Michelandrea
AU - Sbarra, Stefania
AU - Valdagni, Riccardo
AU - Zaffaroni, Nadia
AU - Gandellini, Paolo
AU - Folini, Marco
PY - 2014/2/15
Y1 - 2014/2/15
N2 - 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.
AB - 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.
KW - Autophagy
KW - Cisplatin
KW - LAMP3
KW - miR-205
KW - Prostate cancer
KW - RAB27A
UR - http://www.scopus.com/inward/record.url?scp=84893731055&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893731055&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2013.12.009
DO - 10.1016/j.bcp.2013.12.009
M3 - Article
C2 - 24370341
AN - SCOPUS:84893731055
VL - 87
SP - 579
EP - 597
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 4
ER -