Bremmer Felix, Jarry Hubertus, Strauß Arne, Behnes Carl Ludwig, Trojan Lutz, Thelen Paul
Institute of Pathology, University Medical Center, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
University Medical Center, University of Göttingen, Göttingen, Germany.
Springerplus. 2014 Oct 1;3:574. doi: 10.1186/2193-1801-3-574. eCollection 2014.
Recent breakthrough therapies targeting androgen receptor signalling in castration resistant prostate cancer (CRPC) involve multifunctional androgen receptor (AR) blockade and exhaustive androgen deprivation. Nevertheless, limitations to an enduring effectiveness of new drugs are anticipated in resistance mechanisms occurring under such treatments. In this study we used CRPC cell models VCaP and LNCaP as well as AR-negative PC-3- and non-neoplastic epithelial BPH-1-cells treated with 5, 10 or 25 μmol/L abiraterone hydrolyzed from abiraterone acetate (AA). The origin of CYP17A1 up-regulation under AA treatment was investigated in CRPC cell models by qRT-PCR and western-blot procedures. AA treatments of AR positive CRPC cell models led to decreased expression of androgen regulated genes such as PSA. In these cells diminished expression of androgen regulated genes was accompanied by an up-regulation of CYP17A1 expression within short-term treatments. No such effects became evident in AR-negative PC-3 cells. AR directed siRNA (siAR) used in VCaP cells significantly reduced mRNA expression and AR protein abundance. Such interference with AR signalling in the absence of abiraterone acetate also caused a marked up-regulation of CYP17A1 expression. Down-regulation of androgen regulated genes occurs in spite of an elevated expression of CYP17A1, the very target enzyme for this drug. CYP17A1 up-regulation already takes place within such short treatments with AA and does not require adaptation events over several cell cycles. CYP17A1 is also up-regulated in the absence of AA when AR signalling is physically eliminated by siAR. These results reveal an immediate counter-regulation of CYP17A1 expression whenever AR-signalling is inhibited adequately but not a persisting adaptation yielding drug resistance.
近期针对去势抵抗性前列腺癌（CRPC）中雄激素受体信号传导的突破性疗法包括多功能雄激素受体（AR）阻断和彻底的雄激素剥夺。然而，预计在这些治疗下出现的耐药机制会限制新药的持久疗效。在本研究中，我们使用了CRPC细胞模型VCaP和LNCaP，以及用从醋酸阿比特龙（AA）水解得到的5、10或25μmol/L阿比特龙处理的AR阴性PC-3细胞和非肿瘤性上皮BPH-1细胞。通过qRT-PCR和蛋白质印迹法在CRPC细胞模型中研究了AA处理下CYP17A1上调的起源。AR阳性CRPC细胞模型的AA处理导致雄激素调节基因如PSA的表达降低。在这些细胞中，短期处理后雄激素调节基因表达的降低伴随着CYP17A1表达的上调。在AR阴性的PC-3细胞中未观察到这种效应。在VCaP细胞中使用的AR靶向小干扰RNA（siAR）显著降低了mRNA表达和AR蛋白丰度。在没有醋酸阿比特龙的情况下对AR信号传导的这种干扰也导致CYP17A1表达的显著上调。尽管该药物的靶酶CYP17A1表达升高，但雄激素调节基因仍下调。CYP17A1在AA的这种短期处理内就已上调，并且不需要在多个细胞周期中发生适应性事件。当通过siAR物理消除AR信号传导时，在没有AA的情况下CYP17A1也会上调。这些结果表明，只要AR信号传导被充分抑制，CYP17A1表达就会立即产生反调节，而不是产生耐药性的持续适应性反应。
