Kokal Miriam, Mirzakhani Kimia, Pungsrinont Thanakorn, Baniahmad Aria
Institute of Human Genetics, Jena University Hospital, 07740 Jena, Germany.
Cancers (Basel). 2020 Jul 8;12(7):1833. doi: 10.3390/cancers12071833.
The androgen receptor (AR) plays a leading role in the control of prostate cancer (PCa) growth. Interestingly, structurally different AR antagonists with distinct mechanisms of antagonism induce cell senescence, a mechanism that inhibits cell cycle progression, and thus seems to be a key cellular response for the treatment of PCa. Surprisingly, while physiological levels of androgens promote growth, supraphysiological androgen levels (SAL) inhibit PCa growth in an AR-dependent manner by inducing cell senescence in cancer cells. Thus, oppositional acting ligands, AR antagonists, and agonists are able to induce cellular senescence in PCa cells, as shown in cell culture model as well as ex vivo in patient tumor samples. This suggests a dual AR-signaling dependent on androgen levels that leads to the paradox of the rational to keep the AR constantly inactivated in order to treat PCa. These observations however opened the option to treat PCa patients with AR antagonists and/or with androgens at supraphysiological levels. The latter is currently used in clinical trials in so-called bipolar androgen therapy (BAT). Notably, cellular senescence is induced by AR antagonists or agonist in both androgen-dependent and castration-resistant PCa (CRPC). Pathway analysis suggests a crosstalk between AR and the non-receptor tyrosine kinase Src-Akt/PKB and the PI3K-mTOR-autophagy signaling in mediating AR-induced cellular senescence in PCa. In this review, we summarize the current knowledge of therapeutic induction and intracellular pathways of AR-mediated cellular senescence.
雄激素受体（AR）在前列腺癌（PCa）生长的控制中起主导作用。有趣的是，具有不同拮抗机制的结构不同的AR拮抗剂会诱导细胞衰老，这是一种抑制细胞周期进程的机制，因此似乎是治疗PCa的关键细胞反应。令人惊讶的是，虽然生理水平的雄激素促进生长，但超生理雄激素水平（SAL）通过诱导癌细胞衰老以AR依赖的方式抑制PCa生长。因此，具有相反作用的配体、AR拮抗剂和激动剂能够在PCa细胞中诱导细胞衰老，如细胞培养模型以及患者肿瘤样本的体外实验所示。这表明存在一种依赖雄激素水平的双重AR信号传导，导致了为治疗PCa而使AR持续失活这一合理性的矛盾。然而，这些观察结果为使用AR拮抗剂和/或超生理水平的雄激素治疗PCa患者提供了选择。后者目前用于所谓的双相雄激素疗法（BAT）的临床试验中。值得注意的是，AR拮抗剂或激动剂在雄激素依赖性和去势抵抗性PCa（CRPC）中均能诱导细胞衰老。通路分析表明，在介导PCa中AR诱导的细胞衰老过程中，AR与非受体酪氨酸激酶Src-Akt/PKB以及PI3K-mTOR-自噬信号之间存在相互作用。在本综述中，我们总结了AR介导的细胞衰老的治疗诱导和细胞内途径的当前知识。
