Logan Ian R, McClurg Urszula L, Jones Dominic L, O'Neill Daniel J, Shaheen Fadhel S, Lunec John, Gaughan Luke, Robson Craig N
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
Oncotarget. 2016 Nov 15;7(46):74724-74733. doi: 10.18632/oncotarget.12542.
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.
抑制雄激素受体（AR）信号传导是前列腺癌的传统医学治疗方法。最终这种治疗会失败，因为肿瘤会发展出一种无法治愈的去势抵抗表型，导致前列腺癌对新治疗方法存在未满足的需求。AR在去势抵抗性疾病中仍然是一个可行的治疗靶点，因此下调AR活性的新方法作为潜在治疗方法很有吸引力。在这里，我们描述了一种机制，通过该机制MDM2拮抗剂Nutlin-3可以下调AR，导致促生存的c-FLIP基因表达丧失和细胞凋亡。我们还表明，c-FLIP的缺失使前列腺癌细胞对Nutlin-3敏感。最后，我们证明不相关的MDM2拮抗剂Mi-63也会影响AR信号传导，支持了用MDM2拮抗剂未来治疗前列腺癌的概念。
