Zhu Hanneng, Mazor Michal, Kawano Yoshiaki, Walker Marjorie M, Leung Hing Y, Armstrong Kelly, Waxman Jonathan, Kypta Robert M
Prostate Cancer Research Group, Department of Cancer Cell Biology, Division of Medicine, Imperial College London, United Kingdom.
Cancer Res. 2004 Nov 1;64(21):7918-26. doi: 10.1158/0008-5472.CAN-04-2704.
The Wnt signaling pathway is aberrantly activated in many tumor types, including those of the prostate, in which beta-catenin accumulates in cell nuclei and acts as a transcriptional coregulator for the androgen receptor. Because activating mutations in the beta-catenin gene are rare in prostate cancer, we have looked for altered expression of other components of the Wnt signaling pathway in prostate cancer cells. Here we determined the expression levels of Wnt family genes in cultured human prostate cells and prostate cancer cell lines. We found that WNT11 expression is elevated in hormone-independent prostate cancer cell lines. Additional analysis indicated that WNT11 expression is also elevated in high-grade prostatic tumors and in hormone-independent xenografts. Growth of hormone-dependent LNCaP cells in hormone-depleted media led to increased WNT11 expression, which was repressed by the synthetic androgen R1881. This repression was inhibited by the antiandrogen bicalutamide, suggesting that androgens negatively regulate WNT11 expression through the androgen receptor. Expression of WNT11 inhibited androgen receptor transcriptional activity and cell growth in androgen-dependent cells but not in androgen-independent cells. WNT11 inhibited activation of the canonical Wnt pathway by WNT3A in HEK 293 cells and inhibited basal beta-catenin/Tcf transcriptional activity in LNCaP cells. However, expression of stabilized beta-catenin did not prevent the inhibition of androgen receptor transcriptional activity by WNT11. Our observations are consistent with a model in which androgen depletion activates WNT11-dependent signals that inhibit androgen-dependent but not androgen-independent cell growth.
Wnt信号通路在包括前列腺癌在内的多种肿瘤类型中异常激活，在前列腺癌中，β-连环蛋白在细胞核中积累，并作为雄激素受体的转录共调节因子发挥作用。由于β-连环蛋白基因的激活突变在前列腺癌中很少见，我们一直在寻找前列腺癌细胞中Wnt信号通路其他成分的表达改变情况。在此，我们测定了培养的人前列腺细胞和前列腺癌细胞系中Wnt家族基因的表达水平。我们发现，WNT11在激素非依赖性前列腺癌细胞系中的表达升高。进一步分析表明，WNT11在高级别前列腺肿瘤和激素非依赖性异种移植瘤中的表达也升高。激素依赖性LNCaP细胞在激素缺乏培养基中生长导致WNT11表达增加，而合成雄激素R1881可抑制这种增加。抗雄激素比卡鲁胺可抑制这种抑制作用，提示雄激素通过雄激素受体对WNT11表达起负调节作用。WNT11的表达抑制雄激素依赖性细胞中的雄激素受体转录活性和细胞生长，但对激素非依赖性细胞无此作用。WNT11在HEK 293细胞中抑制WNT3A介导的经典Wnt通路激活，并在LNCaP细胞中抑制基础β-连环蛋白/Tcf转录活性。然而，稳定表达的β-连环蛋白并不能阻止WNT11对雄激素受体转录活性的抑制作用。我们的观察结果与一个模型相符，即雄激素耗竭激活WNT11依赖性信号，该信号抑制雄激素依赖性而非激素非依赖性细胞生长。
