Wilson Sarah, Cavero Lucia, Tong Dali, Liu Qiuli, Geary Kyla, Talamonti Nicholas, Xu Jing, Fu Junjiang, Jiang Jun, Zhang Dianzheng
Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania 19131, USA.
Center for Chronic Disorders of Aging, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania 19131, USA.
Oncotarget. 2017 May 19;8(33):54683-54693. doi: 10.18632/oncotarget.18003. eCollection 2017 Aug 15.
Although androgen deprivation therapy (ADT) serves as the primary treatment option for localized or metastatic prostate cancer, most cases eventually develop into castration-resistant prostate cancer (CRPC). However, androgen receptor (AR) continues to be functional in CRPC through various mechanisms, including the development of AR splicing variants, especially ARV7. Since it lacks the ligand binding domain but retains the intact DNA binding domain, ARV7 is constitutively active, which makes ARV7-positive prostate cancer responsive to neither abiraterone nor enzalutamide. In this study, we explored the effect of resveratrol on ARV7 transcriptional activity and the potential for development of resveratrol as a treatment for ARV7-positive prostate cancer. First, we ectopically expressed ARV7 in PC3 cells, an AR-negative prostate cancer cell line, and demonstrated that resveratrol is capable of inhibiting ARV7 transcriptional activity by downregulating ARV7 protein levels. Of note, resveratrol does not affect the mRNA levels of ARV7 nor its nuclear translocation. Next, we demonstrated that resveratrol is capable of downregulating the levels of the endogenously expressed ARV7 as well as AR target gene mRNAs in 22RV1 prostate cancer cells. Mechanistically, resveratrol downregulates ARV7 by enhancing ARV7 polyubiquitination and subsequent proteasome-mediated degradation. These findings suggest that resveratrol could be a potential treatment for ARV7-positive CPRC.
虽然雄激素剥夺疗法（ADT）是局限性或转移性前列腺癌的主要治疗选择，但大多数病例最终会发展为去势抵抗性前列腺癌（CRPC）。然而，雄激素受体（AR）通过多种机制在CRPC中仍然具有功能，包括AR剪接变体的产生，尤其是ARV7。由于ARV7缺乏配体结合域但保留完整的DNA结合域，因此它具有组成性活性，这使得ARV7阳性前列腺癌对阿比特龙和恩杂鲁胺均无反应。在本研究中，我们探讨了白藜芦醇对ARV7转录活性的影响以及白藜芦醇作为ARV7阳性前列腺癌治疗药物的开发潜力。首先，我们在PC3细胞（一种AR阴性前列腺癌细胞系）中异位表达ARV7，并证明白藜芦醇能够通过下调ARV7蛋白水平来抑制ARV7转录活性。值得注意的是，白藜芦醇不影响ARV7的mRNA水平及其核转位。接下来，我们证明白藜芦醇能够下调22RV1前列腺癌细胞中内源性表达的ARV7水平以及AR靶基因mRNA水平。从机制上讲，白藜芦醇通过增强ARV7多聚泛素化以及随后蛋白酶体介导的降解来下调ARV7。这些发现表明白藜芦醇可能是ARV7阳性CRPC的一种潜在治疗方法。
