Cohen Michael B, Rokhlin Oskar W
Department of Pathology, The University of Iowa, Iowa City, Iowa 52242, USA.
J Cell Biochem. 2009 Feb 15;106(3):363-71. doi: 10.1002/jcb.22022.
Recent reports have shown that the AR is the key determinant of the molecular changes required for driving prostate cancer cells from an androgen-dependent to an androgen-independent or androgen depletion-independent (ADI) state. Several recent publications suggest that down-regulation of AR expression should therefore be considered the principal strategy for the treatment of ADI prostate cancer. However, no valid data is available about how androgen-dependent prostate cancer cells respond to apoptosis-inducing drugs after knocking down AR expression and whether prostate cancer cells escape apoptosis after inhibition of AR expression. This review will focus on mechanisms of prostate cancer cell survival after inhibition of AR activity mediated either by androgen depletion or by targeting the expression of AR by siRNA. We have shown that knocking down AR expression by siRNA induced PI3K-independent activation of Akt, which was mediated by calcium/calmodulin-dependent kinase II (CaMKII). We also showed that the expression of CaMKII genes is under AR control: active AR in the presence of androgens inhibits CaMKII gene expression whereas inhibition of AR activity results in an elevated level of kinase activity and in enhanced expression of CaMKII genes. This in turn activates the anti-apoptotic PI3K/Akt pathways. CaMKII also express anti-apoptotic activity that is independent from the Akt pathway. This may therefore be an important mechanism by which prostate cancer cells escape apoptosis after androgen depletion or knocking down AR expression. In addition, we have found that there is another way to escape cell death after AR inhibition: DNA damaging agents cannot fully activate p53 in the absence of AR and as a result p53 down stream targets, for example, microRNA-34, cannot be activated and induce apoptosis. This implies that there may be a need for re-evaluation of the therapeutic approaches to human prostate cancer.
最近的报告显示，雄激素受体（AR）是驱动前列腺癌细胞从雄激素依赖状态转变为雄激素非依赖或雄激素耗竭非依赖（ADI）状态所需分子变化的关键决定因素。最近的几篇出版物表明，因此，下调AR表达应被视为治疗ADI前列腺癌的主要策略。然而，关于雄激素依赖的前列腺癌细胞在敲低AR表达后对凋亡诱导药物的反应，以及AR表达被抑制后前列腺癌细胞是否逃避凋亡，尚无有效数据。本综述将聚焦于通过雄激素耗竭或通过小干扰RNA（siRNA）靶向AR表达介导抑制AR活性后前列腺癌细胞存活的机制。我们已经表明，通过siRNA敲低AR表达可诱导不依赖磷脂酰肌醇-3激酶（PI3K）的蛋白激酶B（Akt）激活，这是由钙/钙调蛋白依赖性激酶II（CaMKII）介导的。我们还表明，CaMKII基因的表达受AR控制：在雄激素存在下活性AR抑制CaMKII基因表达，而抑制AR活性则导致激酶活性水平升高和CaMKII基因表达增强。这进而激活抗凋亡的PI3K/Akt信号通路。CaMKII还表达独立于Akt信号通路的抗凋亡活性。因此，这可能是前列腺癌细胞在雄激素耗竭或敲低AR表达后逃避凋亡的重要机制。此外，我们发现AR抑制后还有另一种逃避细胞死亡的方式：在没有AR的情况下，DNA损伤剂不能完全激活p53，结果p53的下游靶点，例如微小RNA-34，不能被激活并诱导凋亡。这意味着可能需要重新评估人类前列腺癌的治疗方法。
