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

Lookup NU author(s): Dr Ian Logan, Dr Urszula McClurg, Dr Dominic Jones, Daniel O'Neill, Dr Fadhel Shaheen, Professor John LunecORCiD, Dr Luke GaughanORCiD, Professor Craig Robson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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.

Publication metadata

Author(s): Logan IR, McClurg UL, Jones DL, O'Neill DJ, Shaheen FS, Lunec J, Gaughan L, Robson CN

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2016

Volume: 7

Issue: 46

Pages: 74724-74733

Online publication date: 09/10/2016

Acceptance date: 26/09/2016

Date deposited: 18/04/2017

ISSN (electronic): 1949-2553

Publisher: Impact Journal LLC

URL: http://dx.doi.org/10.18632/oncotarget.12542

DOI: 10.18632/oncotarget.12542

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