Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
FASEB J. 2022 Sep;36(9):e22495. doi: 10.1096/fj.202200190R.
In the treatment of patients with locally advanced prostate cancer (PCa), androgen deprivation therapy (ADT) significantly enhances the efficacy of radiotherapy by weakening the DNA damage response (DDR) pathway. Recently, several studies have suggested that androgen receptor splicing variants (ARvs) may mediate a compensatory DDR pathway when canonical androgen receptor (AR) signaling is inhibited, thus contributing to the resistance of some patients to this combinational treatment. However, the specific roles of certain ARvs as well as the detailed mechanism of how ARvs regulate the DDR are not well understood. Here, we demonstrated that AR splicing variant 7 (ARv7), which is the most abundant form of ARvs, significantly promotes the DDR of PCa cells under severe DNA damage independent of its parental AR by using the ionizing radiation (IR) and doxorubicin (Dox)-treated cell models. Mechanistically, ARv7 is sufficient to upregulate both the homologous recombination (HR) and the nonhomologous end joining (NHEJ) pathways by forming a positive regulatory loop with poly ADP-ribose polymerase 1 (PARP1). Moreover, the presence of ARv7 impairs the synergistic effect between AR antagonists and poly ADP-ribose polymerase (PARP) inhibitor, which has been recently shown to be a promising future treatment strategy for metastatic castration resistant prostate cancer (mCRPC). Combined, our data indicate that constitutively active ARv7 not only contributes to radioresistance after ADT, but may also serve as a potential predictive biomarker for assessing the efficacy of novel PARP inhibitor-based therapy in PCa.
在局部晚期前列腺癌（PCa）患者的治疗中，雄激素剥夺疗法（ADT）通过削弱 DNA 损伤反应（DDR）途径显著增强了放疗的疗效。最近，几项研究表明，当经典的雄激素受体（AR）信号被抑制时，雄激素受体剪接变体（ARvs）可能介导一种补偿性的 DDR 途径，从而导致一些患者对这种联合治疗产生抵抗。然而，某些 ARvs 的具体作用以及 ARvs 如何调节 DDR 的详细机制尚不清楚。在这里，我们通过使用电离辐射（IR）和阿霉素（Dox）处理的细胞模型，证明了最丰富的 ARvs 形式 AR 剪接变体 7（ARv7）在严重的 DNA 损伤下，独立于其亲本 AR，显著促进了 PCa 细胞的 DDR。从机制上讲，ARv7 通过与聚 ADP-核糖聚合酶 1（PARP1）形成正反馈环，足以上调同源重组（HR）和非同源末端连接（NHEJ）途径。此外，ARv7 的存在会损害 AR 拮抗剂和聚 ADP-核糖聚合酶（PARP）抑制剂之间的协同作用，最近已证明这是转移性去势抵抗性前列腺癌（mCRPC）的一种很有前途的未来治疗策略。综上所述，我们的数据表明，组成性激活的 ARv7 不仅有助于 ADT 后的放射抵抗，而且还可能作为评估新型 PARP 抑制剂为基础的治疗在 PCa 中的疗效的潜在预测生物标志物。
