Lee Soo Ok, Lou Wei, Hou Min, Onate Sergio A, Gao Allen C
Department of Medicine and Pharmacology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Oncogene. 2003 Sep 11;22(39):7981-8. doi: 10.1038/sj.onc.1206735.
Androgen receptor (AR) plays an important role in the development and progression of prostate cancer upon the action of androgen through the binding of the androgen-responsive elements (AREs) on the target genes. Abnormal activation of the AR by nonandrogen has been implicated in the progression of androgen-independent prostate cancer. The levels of interleukin-4 (IL-4) are significantly elevated in sera of patients with hormone refractory prostate cancer. The potential role of IL-4 on the activation of AR was investigated in prostate cancer cells. IL-4 enhances AR-mediated prostate-specific antigen (PSA) expression and ARE-containing gene activity through activation of the AR in the androgen ablation condition in human prostate cancer cells. The AR can also be sensitized by IL-4 and activated by significantly lower levels of androgen (10 pM of R1881) in prostate cancer cells. IL-4 enhances nuclear translocation of AR and increases binding of the AR to the ARE in LNCaP prostate cancer cells. Blocking of the Akt pathway by an Akt-specific inhibitor LY294002 abrogates IL-4-induced PSA expression and AR signaling. These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells. Understanding IL-4-induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen-independent progression of prostate cancer cells.
雄激素受体（AR）在雄激素作用下，通过与靶基因上的雄激素反应元件（AREs）结合，在前列腺癌的发生和发展中发挥重要作用。非雄激素对AR的异常激活与去势抵抗性前列腺癌的进展有关。激素难治性前列腺癌患者血清中白细胞介素-4（IL-4）水平显著升高。研究了IL-4在前列腺癌细胞中对AR激活的潜在作用。在人前列腺癌细胞的雄激素剥夺条件下，IL-4通过激活AR增强AR介导的前列腺特异性抗原（PSA）表达和含ARE基因的活性。在前列腺癌细胞中，IL-4还可使AR敏感，并被显著较低水平的雄激素（10 pM的R1881）激活。IL-4增强LNCaP前列腺癌细胞中AR的核转位，并增加AR与ARE的结合。用Akt特异性抑制剂LY294002阻断Akt通路可消除IL-4诱导的PSA表达和AR信号传导。这些结果表明，IL-4通过激活LNCaP前列腺癌细胞中的AR和Akt信号通路增强PSA表达。了解IL-4诱导的导致AR异常激活的信号传导将为前列腺癌细胞去势抵抗进展的分子机制提供见解。
