Nutlin-3 inhibits androgen receptor-driven c-FLIP expression, resulting in apoptosis of prostate cancer cells

Logan, Ian R, McClurg, Urszula L ORCID: 0000-0003-2631-4174, Jones, Dominic L, O'Neill, Daniel J, Shaheen, Fadhel S, Lunec, John, Gaughan, Luke and Robson, Craig N (2016) Nutlin-3 inhibits androgen receptor-driven c-FLIP expression, resulting in apoptosis of prostate cancer cells. ONCOTARGET, 7 (46). pp. 74724-74733.

Text Nutlin-3 inhibits androgen receptor-driven c-FLIP expression, resulting in apoptosis of prostate cancer cells.pdf - Author Accepted Manuscript Download (2MB)

Abstract

Inhibition of androgen receptor (AR) signalling represents the conventional medical management of prostate cancer. Ultimately this treatment fails because tumors develop an incurable, castrate resistant phenotype, resulting in an unmet need for new treatments in prostate cancer. The AR remains a viable therapeutic target in castrate resistant disease, such that novel ways of downregulating AR activities are attractive as potential treatments. Here we describe a mechanism by which the AR can be downregulated by the MDM2 antagonist Nutlin-3, resulting in loss of pro-survival c-FLIP gene expression and apoptosis. We additionally show that loss of c-FLIP sensitises prostate cancer cells to Nutlin-3. Finally, we demonstrate that the unrelated MDM2 antagonist Mi-63 also impinges upon AR signalling, supporting the concept of future treatment of prostate cancer with MDM2 antagonists.

Item Type:	Article
Uncontrolled Keywords:	prostate cancer, MDM2, androgen receptor, c-FLIP, anti-androgens
Depositing User:	Symplectic Admin
Date Deposited:	06 Nov 2018 12:47
Last Modified:	19 Jan 2023 01:13
DOI:	10.18632/oncotarget.12542
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3028465