Yang Zhiming, Chang Yu-Jia, Yu I-Chen, Yeh Shuyuan, Wu Cheng-Chia, Miyamoto Hiroshi, Merry Diane E, Sobue Gen, Chen Lu-Min, Chang Shu-Shi, Chang Chawnshang
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
Nat Med. 2007 Mar;13(3):348-53. doi: 10.1038/nm1547. Epub 2007 Mar 4.
Motor neuron degeneration resulting from the aggregation of the androgen receptor with an expanded polyglutamine tract (AR-polyQ) has been linked to the development of spinal and bulbar muscular atrophy (SBMA or Kennedy disease). Here we report that adding 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction between AR and its coregulators, and also increases cell survival by decreasing AR-polyQ nuclear aggregation and increasing AR-polyQ degradation in cultured cells. Intraperitoneal injection of ASC-J9 into AR-polyQ transgenic SBMA mice markedly improved disease symptoms, as seen by a reduction in muscular atrophy. Notably, unlike previous approaches in which surgical or chemical castration was used to reduce SBMA symptoms, ASC-J9 treatment ameliorated SBMA symptoms by decreasing AR-97Q aggregation and increasing VEGF164 expression with little change of serum testosterone. Moreover, mice treated with ASC-J9 retained normal sexual function and fertility. Collectively, our results point to a better therapeutic and preventative approach to treating SBMA, by disrupting the interaction between AR and AR coregulators.
雄激素受体与扩展的聚谷氨酰胺链（AR-polyQ）聚集导致的运动神经元变性与脊髓和延髓性肌萎缩（SBMA或肯尼迪病）的发展有关。在此我们报告，添加5-羟基-1,7-双（3,4-二甲氧基苯基）-1,4,6-庚三烯-3-酮（ASC-J9）可破坏AR与其共调节因子之间的相互作用，并且通过减少培养细胞中AR-polyQ的核聚集和增加AR-polyQ的降解来提高细胞存活率。向AR-polyQ转基因SBMA小鼠腹腔注射ASC-J9可显著改善疾病症状，如肌肉萎缩减轻所示。值得注意的是，与以往使用手术或化学去势来减轻SBMA症状的方法不同，ASC-J9治疗通过减少AR-97Q聚集和增加VEGF164表达来改善SBMA症状，而血清睾酮变化很小。此外，接受ASC-J9治疗的小鼠保留了正常的性功能和生育能力。总体而言，我们的结果表明，通过破坏AR与AR共调节因子之间的相互作用，有望找到一种更好的治疗和预防SBMA的方法。
