Ambra1 induces autophagy and desensitizes human prostate cancer cells to cisplatin.

Prostate cancer (PCa), the second most mortal cancer from developed countries, presents a high level of chemo-resistance. There is emerging evidence underscores the critical role of autophagy in the onset, progression and chemo-resistance of PCa. In the present study, we investigated the possible role of a novel autophagy regulator, Activating Molecule in Beclin1-Regulated Autophagy1 (Ambra1), a novel ATG gene in the sensitivity or PCa cells to cisplatin. We explored the regulation by the Ambra1 manipulation on the induction of apoptosis and autophagy in human PCa DU145 cells in the presence of cisplatin, via up- or down-regulating Ambra1 expression. In addition, we examined the colony forming of DU145 cells post cisplatin treatment and Ambra1 manipulation. Our results demonstrated that the Ambra1 upregulation reduced, whereas Ambra1 knockdown increased the cisplatin-induced apoptosis, caspase 3 cleavage and PARP (poly ADP-ribose polymerase) cleavage. Interestingly, we also found significant autophagy induction in the cisplatin-treated DU145 cells, with increased autophagic vesicles, upregulated autophagy-related markers. However, the cisplatin-induced autophagy was upregulated by the Ambra1 overexpression or was downregulated  by the Ambra1 knockdown. In addition, the colony forming was also positively regulated by Ambra1 in DU145 cells post cisplatin treatment. In conclusion, Ambra1 negatively regulates the cisplatin-induced apoptosis and the cisplatin-mediated growth reduction in DU145 cells, in association with the Ambra1-mediated autophagy promotion. It implies that Ambra1-mediated autophagy might be an important mechanism underlining the sensitivity reduction of PCa cells.