McClurg Urszula L, Azizyan Mahsa, Dransfield Daniel T, Namdev Nivedita, Chit Nay C T H, Nakjang Sirintra, Robson Craig N
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Oncotarget. 2018 May 18;9(38):24992-25007. doi: 10.18632/oncotarget.25167.
Metastatic castration resistant prostate cancer is one of the main causes of male cancer associated deaths worldwide. Development of resistance is inevitable in patients treated with anti-androgen therapies. This highlights a need for novel therapeutic strategies that would be aimed upstream of the androgen receptor (AR). Here we report that the novel small molecule anti-androgen, galeterone targets USP12 and USP46, two highly homologous deubiquitinating enzymes that control the AR-AKT-MDM2-P53 signalling pathway. Consequently, galeterone is effective in multiple models of prostate cancer including both castrate resistant and AR-negative prostate cancer. However, we have observed that USP12 and USP46 selectively regulate full length AR protein but not the AR variants. This is the first report of deubiquitinating enzyme targeting as a strategy in prostate cancer treatment which we show to be effective in multiple, currently incurable models of this disease.
转移性去势抵抗性前列腺癌是全球男性癌症相关死亡的主要原因之一。接受抗雄激素治疗的患者不可避免地会产生耐药性。这凸显了对旨在作用于雄激素受体（AR）上游的新型治疗策略的需求。在此，我们报告新型小分子抗雄激素药物加列酮靶向USP12和USP46，这两种高度同源的去泛素化酶可控制AR-AKT-MDM2-P53信号通路。因此，加列酮在多种前列腺癌模型中均有效，包括去势抵抗性和AR阴性前列腺癌。然而，我们观察到USP12和USP46选择性调节全长AR蛋白，而非AR变体。这是首次报道将靶向去泛素化酶作为前列腺癌治疗策略，我们证明其在该疾病的多种目前无法治愈的模型中均有效。
