Sun C, Shi Y, Xu L L, Nageswararao C, Davis L D, Segawa T, Dobi A, McLeod D G, Srivastava S
Center for Prostate Disease Research (CPDR), Department of Surgery, Uniformed Services University, Rockville, MD 20852, USA.
Oncogene. 2006 Jun 29;25(28):3905-13. doi: 10.1038/sj.onc.1209424. Epub 2006 Apr 24.
Alteration of the AR functions due to amplification, overexpression and somatic mutation of the AR itself or altered interaction of AR with other cell growth regulatory proteins, may contribute to a significant subset of advanced prostate cancer (CaP). Very little is known about the pathways impacted by AR dysfunctions, although CaP associated AR alterations suggest the biological role of the AR dysfunction in disease progression. Comparative evaluations of wild type (wt) AR and mutant (mt) ARs in appropriate experimental models should provide a better understanding of the functional impact of AR alterations in CaP. Here, we provide direct evidence showing cell growth/cell survival promoting effects of the widely studied CaP associated AR mutation (T877A). In contrast to Ad-wtAR or Ad-control infected LNCaP or LAPC4 cells, Ad-mtAR (T877A) infected LNCaP or LAPC4 cells continued to grow in the androgen-deprived medium and exhibited an androgen independent AR-transcription factor activity. Further, Ad-mtAR (T877A) infected LNCaP or LAPC4 cells exhibited enhanced cell growth in the presence of lower concentrations of the synthetic androgen, R1881. Of note, Ad-mtAR (T877A) infected LNCaP cells showed striking resistance to cell growth inhibition/apoptosis mediated by the wt p53. Taken together, these findings provide novel insights into the AR dysfunctions resulting from the T877A mutation and functionally similar AR alterations may provide selective cell growth/survival advantage for CaP progression. These observations have important implications for developing biology-based prognostic biomarkers and therapeutic strategies for CaP showing such AR dysfunctions.
雄激素受体（AR）自身的扩增、过表达和体细胞突变，或AR与其他细胞生长调节蛋白相互作用的改变，导致AR功能改变，这可能在相当一部分晚期前列腺癌（CaP）中起作用。尽管与CaP相关的AR改变提示了AR功能障碍在疾病进展中的生物学作用，但关于AR功能障碍所影响的信号通路却知之甚少。在合适的实验模型中对野生型（wt）AR和突变型（mt）AR进行比较评估，应该能更好地理解AR改变对CaP的功能影响。在此，我们提供直接证据表明，广泛研究的与CaP相关的AR突变（T877A）具有促进细胞生长/细胞存活的作用。与腺病毒-wtAR或腺病毒对照感染的LNCaP或LAPC4细胞不同，腺病毒-mtAR（T877A）感染的LNCaP或LAPC4细胞在雄激素剥夺培养基中继续生长，并表现出雄激素非依赖性的AR转录因子活性。此外，腺病毒-mtAR（T877A）感染的LNCaP或LAPC4细胞在较低浓度的合成雄激素R1881存在下表现出增强的细胞生长。值得注意的是，腺病毒-mtAR（T877A）感染的LNCaP细胞对wt p53介导的细胞生长抑制/凋亡具有显著抗性。综上所述，这些发现为T877A突变导致的AR功能障碍提供了新的见解，功能相似的AR改变可能为CaP进展提供选择性的细胞生长/存活优势。这些观察结果对于开发基于生物学的预后生物标志物以及针对表现出此类AR功能障碍的CaP的治疗策略具有重要意义。
