Nutlin-3 inhibits androgen receptor-driven c-FLIP expression, resulting in apoptosis of prostate cancer cells
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Ian R. Logan1, Urszula L. McClurg1, Dominic L. Jones1, Daniel J. O’Neill1, Fadhel S. Shaheen1, John Lunec1, Luke Gaughan1 and Craig N. Robson1
1 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom
Luke Gaughan, email:
Keywords: prostate cancer, MDM2, androgen receptor, c-FLIP, anti-androgens
Received: September 18, 2016 Accepted: September 26, 2016 Published: October 09, 2016
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.
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