Liu Chengfei, Nadiminty Nagalakshmi, Tummala Ramakumar, Chun Jae Yeon, Lou Wei, Zhu Yezi, Sun Meng, Evans Christopher P, Zhou Qinghua, Gao Allen C
Department of Urology, University of California at Davis, Sacramento, CA, USA.
Genes Cancer. 2011 Feb;2(2):151-9. doi: 10.1177/1947601911409744.
Androgen receptor (AR) signaling not only plays a pivotal role in the development of androgen-dependent prostate cancer but is also important in the growth and survival of castration-resistant prostate cancer (CRPC). The first line of treatment of androgen-dependent prostate cancer is the use of androgen deprivation therapy. However, most patients will eventually relapse due to development of CRPC. Thus, development of a strategy to target AR for treatment of CRPC is urgently needed. The authors have previously identified andrographolide as an inhibitor of interleukin-6, which can suppress tumor growth of prostate cancer cells by screening compounds from the Prestwick Natural compound library. In this study, they identified that andrographolide can inhibit AR expression and prostate cancer cell growth and induce apoptosis. Andrographolide is able to down-regulate AR expression at both mRNA and protein levels, prevents its nuclear translocation, and inhibits transactivation of its target genes. Andrographolide prevents the binding of Hsp90 to AR, resulting in proteasome-mediated AR degradation. Furthermore, andrographolide inhibits castration-resistant C4-2 cell growth by reducing AR expression and activity. Thus, andrographolide can be developed as a potential therapeutic agent for prostate cancer by inhibition of androgen receptor signaling.
雄激素受体（AR）信号传导不仅在雄激素依赖性前列腺癌的发展中起关键作用，而且在去势抵抗性前列腺癌（CRPC）的生长和存活中也很重要。雄激素依赖性前列腺癌的一线治疗方法是使用雄激素剥夺疗法。然而，大多数患者最终会因CRPC的发展而复发。因此，迫切需要开发一种靶向AR治疗CRPC的策略。作者此前已鉴定穿心莲内酯为白细胞介素-6的抑制剂，其可通过从Prestwick天然化合物库中筛选化合物来抑制前列腺癌细胞的肿瘤生长。在本研究中，他们发现穿心莲内酯可抑制AR表达和前列腺癌细胞生长并诱导凋亡。穿心莲内酯能够在mRNA和蛋白质水平下调AR表达，阻止其核转位，并抑制其靶基因的反式激活。穿心莲内酯可阻止Hsp90与AR结合，导致蛋白酶体介导的AR降解。此外，穿心莲内酯通过降低AR表达和活性来抑制去势抵抗性C4-2细胞生长。因此，穿心莲内酯可通过抑制雄激素受体信号传导开发成为前列腺癌的潜在治疗药物。
