1] Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Oncogene. 2014 Apr 10;33(15):1954-63. doi: 10.1038/onc.2013.143. Epub 2013 Apr 22.
Altered androgen-receptor (AR) expression and/or constitutively active AR are commonly associated with prostate cancer (PCa) progression. Targeting AR remains a focal point for designing new strategy of PCa therapy. Here, we have shown that DAB2IP, a novel tumor suppressor in PCa, can inhibit AR-mediated cell growth and gene activation in PCa cells via distinct mechanisms. DAB2IP inhibits the genomic pathway by preventing AR nuclear translocation or phosphorylation and suppresses the non-genomic pathway via its unique functional domain to inactivate c-Src. Also, DAB2IP is capable of suppressing AR activation in an androgen-independent manner. In addition, DAB2IP can inhibit several AR splice variants showing constitutive activity in PCa cells. In DAB2IP(-/-) mice, the prostate gland exhibits hyperplastic epithelia, in which AR becomes more active. Consistently, DAB2IP expression inversely correlates with AR activation status particularly in recurrent or metastatic PCa patients. Taken together, DAB2IP is a unique intrinsic AR modulator in normal cells, and likely can be further developed into a therapeutic agent for PCa.
雄激素受体（AR）表达的改变和/或组成性激活的 AR 通常与前列腺癌（PCa）的进展相关。靶向 AR 仍然是设计 PCa 治疗新策略的重点。在这里，我们已经表明，DAB2IP，一种 PCa 中的新型肿瘤抑制因子，通过不同的机制可以抑制 PCa 细胞中 AR 介导的细胞生长和基因激活。DAB2IP 通过阻止 AR 核易位或磷酸化来抑制基因组途径，并通过其独特的功能域抑制非基因组途径来使 c-Src 失活。此外，DAB2IP 能够以雄激素非依赖性方式抑制 AR 的激活。此外，DAB2IP 可以抑制几种在 PCa 细胞中具有组成活性的 AR 剪接变体。在 DAB2IP（-/-）小鼠中，前列腺表现出增生的上皮，其中 AR 变得更加活跃。一致地，DAB2IP 的表达与 AR 激活状态呈负相关，特别是在复发性或转移性 PCa 患者中。总之，DAB2IP 是正常细胞中独特的内在 AR 调节剂，可能可以进一步开发为治疗 PCa 的药物。
