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

Jie Liu,Zhiyuan Chen,Lei Wang,Jia Guo,Xiuheng Liu

doi:10.1042/bsr20170770

Jie Liu, Zhiyuan Chen + Show 3 more

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https://doi.org/10.1042/bsr20170770

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Abstract

Prostate cancer (PCa), the second most mortal cancer from developed countries, presents a high level of chemoresistance. There is emerging evidence underscores the critical role of autophagy in the onset, progression, and chemoresistance 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 up-regulation reduced, whereas Ambra1 knockdown increased the cisplatin-induced apoptosis, caspase 3 cleavage, and poly ADP-ribose polymerase (PARP) cleavage. Interestingly, we also found significant autophagy induction in the cisplatin-treated DU145 cells, with increased autophagic vesicles, up-regulated autophagy-related markers. However, the cisplatin-induced autophagy was up-regulated by the Ambra1 overexpression or was down-regulated 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.

Highlights

Prostate cancer (PCa) is the second most mortal cancer after lung cancer in men from developed countries [1]
We investigated the possible role of activating molecule in beclin1-regulated autophagy1 (Ambra1), a novel ATG gene, on the cisplatin-induced apoptosis and cisplatin-mediated growth reduction in human PCa DU145 cells
Our results found the negative regulation by Ambra1 on the cisplatin-induced apoptosis in DU145 cells, regardless of p62 signaling pathway

Summary

Introduction

Prostate cancer (PCa) is the second most mortal cancer after lung cancer in men from developed countries [1]. Though the androgen deprivation therapy and chemotherapy can control the primary tumor growth in the tumor’s early stages, some patients are resistant (not sensitive) to castration or chemoresistant, needing for more effective treatments [2,3]. In terms of the chemoresistance of PCa, multiple mechanisms have been emphasized. Androgen receptor (AR) axis [4,5], ATP-binding cassette sub-family G member 2 (ABCG2) [6,7] have indicated to promote the drug-resistant activity in human PCa, via several pivotal signaling pathways. Multiple autophagy-related proteins have been found to overexpress and to associate with local tumor aggression in the lung, breast, melanoma, and other tumors [8,9]. In PCa, autophagy has been proposed either as determinant or drug target [10,11,12]

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