title: Nutlin-3 inhibits androgen receptor-driven c-FLIP expression, resulting in apoptosis of prostate cancer cells.
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.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Logan
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: Urszula L
authors.initials: UL
authors.lastname: McClurg
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: Dominic L
authors.initials: DL
authors.lastname: Jones
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Neill
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: Fadhel S
authors.initials: FS
authors.lastname: Shaheen
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Lunec
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D015415:Biomarkers; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D015415:Biomarkers; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D007093:Imidazoles; D010879:Piperazines; D011944:Receptors, Androgen; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; androgen receptor; anti-androgens; c-FLIP; prostate cancer