Knuuttila Matias, Mehmood Arfa, Huhtaniemi Riikka, Yatkin Emrah, Häkkinen Merja R, Oksala Riikka, Laajala Teemu D, Ryberg Henrik, Handelsman David J, Aittokallio Tero, Auriola Seppo, Ohlsson Claes, Laiho Asta, Elo Laura L, Sipilä Petra, Mäkelä Sari I, Poutanen Matti
Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Am J Pathol. 2018 Jan;188(1):216-228. doi: 10.1016/j.ajpath.2017.08.036. Epub 2017 Nov 7.
The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that, similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Herein, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P < 0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (twofold, P < 0.05) and the AR splice variants 1 (threefold, P < 0.05) and 7 (threefold, P < 0.01) were further increased in the antiandrogen-treated tumors. Nonsignificant effects were observed in the expression of certain classic androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen-regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that, besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels.
去势抵抗性前列腺癌（CRPC）的发展与肿瘤内雄激素生物合成的激活以及雄激素受体（AR）表达的增加有关。我们最近证明，与临床CRPC相似，原位生长的去势抵抗性VCaP（CR-VCaP）异种移植瘤表达高水平的AR，并保持与完整小鼠体内生长的肿瘤相似的肿瘤内雄激素浓度。在此，我们表明抗雄激素治疗（恩杂鲁胺或ARN-509）显著降低了（10倍，P < 0.01）CR-VCaP肿瘤内的睾酮和双氢睾酮浓度，表明肿瘤内雄激素的减少是抗雄激素在CRPC中介导其作用的一种新机制。抗雄激素治疗还改变了多种可能参与类固醇代谢的酶的表达。与临床CRPC相同，在抗雄激素治疗的肿瘤中，全长AR（两倍，P < 0.05）以及AR剪接变体1（三倍，P < 0.05）和7（三倍，P < 0.01）的表达水平进一步增加。尽管睾酮和双氢睾酮水平较低，但在某些经典雄激素调节基因（如TMPRSS2和KLK3）的表达中未观察到显著影响。然而，最近确定对雄激素调节的AR作用高度敏感的其他基因，如NOV和ST6GalNAc1，发生了明显改变，这表明雄激素作用降低。综上所述，数据表明，除了阻断AR外，抗雄激素在多个水平上改变了CR-VCaP异种移植瘤中的雄激素信号传导。
