Department of Urology, and Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
Cancer Res. 2010 Apr 15;70(8):3309-19. doi: 10.1158/0008-5472.CAN-09-3703. Epub 2010 Apr 13.
Prostate cancer initiation and progression are uniquely dependent on the androgen receptor (AR). Even when the cancer progresses to a castration-resistant stage, AR signaling remains active via a variety of mechanisms. In the present study, we showed that NF-kappaB/p52 can activate the AR, resulting in increased transactivation of AR-responsive genes, such as PSA and NKX3.1, in a ligand-independent manner. NF-kappaB2/p52 enhances nuclear translocation and activation of AR by interacting with its NH(2)-terminal domain and enhances the recruitment of coactivators such as p300 to the promoters of AR-dependent genes. These results were confirmed in three different prostate cancer cell lines: LAPC-4 (wild-type AR), LNCaP (mutant AR), and C4-2 (castration resistant). Transfection of p52 into LAPC-4 and LNCaP cells (which express low levels of p52) showed increased activation of the endogenous AR. Downregulation of endogenous p52 in C4-2 cells resulted in abrogation of AR constitutive activation. Comparison of the relative effects of p52 and p65 (RelA) showed that p52, but not p65, could activate the AR. Collectively, these findings, together with previous reports that the levels of NF-kappaB2/p52 are elevated in prostate cancer cells and that active NF-kappaB2/p52 promotes prostate cancer cell growth in vitro and in vivo, suggest that NF-kappaB2/p52 may play a critical role in the progression of castration-resistant prostate cancer.
前列腺癌的发生和发展独特地依赖于雄激素受体 (AR)。即使癌症发展到去势抵抗阶段，AR 信号仍然通过多种机制保持活跃。在本研究中，我们表明 NF-κB/p52 可以激活 AR，导致 PSA 和 NKX3.1 等 AR 反应基因的转录激活增加，呈配体非依赖性方式。NF-κB2/p52 通过与 AR 的 NH2-末端结构域相互作用，增强 AR 的核易位和激活，并增强共激活子如 p300 募集到 AR 依赖性基因的启动子上。这些结果在三种不同的前列腺癌细胞系中得到了证实：LAPC-4（野生型 AR）、LNCaP（突变型 AR）和 C4-2（去势抵抗）。将 p52 转染到 LAPC-4 和 LNCaP 细胞（表达低水平的 p52）中，显示内源性 AR 的激活增加。C4-2 细胞中内源性 p52 的下调导致 AR 组成性激活的中止。比较 p52 和 p65（RelA）的相对作用表明，p52 而不是 p65 可以激活 AR。总之，这些发现与先前的报告一致，即 NF-κB2/p52 的水平在前列腺癌细胞中升高，并且活性 NF-κB2/p52 促进体外和体内前列腺癌细胞的生长，表明 NF-κB2/p52 可能在去势抵抗性前列腺癌的进展中发挥关键作用。
