White button mushroom (Agaricus bisporus) disrupts androgen receptor signaling in human prostate cancer cells and patient-derived xenograft.
White button mushroom (Agaricus bisporus) disrupts androgen receptor signaling in human prostate cancer cells and patient-derived xenograft.
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白色蘑菇（双孢蘑菇）破坏人前列腺癌细胞和患者来源的异种移植物中的雄激素受体信号传导。
DOI：
10.1016/j.jnutbio.2020.108580
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Wang X;Ha D;Mori H;Chen S
白色双孢蘑菇（Agaricus bisporus）是一种潜在的前列腺癌化学预防和治疗药物。我们在生化复发性PCa患者中进行的WBM粉末I期临床试验表明，WBM摄入可降低前列腺特异性抗原（PSA）的循环水平。我们假设WBM通过雄激素受体（AR）信号传导轴对PCa发挥作用。因此，我们用雄激素依赖性PCa细胞系（LNCaP和VCaP）和来自前列腺肿瘤（TM 00298）的患者源性异种移植物（PDX）进行了逆转录研究。western blot和qRT-PCR检测结果表明，WBM提取物（6~30 mg/mL）对DHT诱导的LNCaP和VCaP细胞PSA表达和细胞增殖均有抑制作用，且呈剂量依赖性。免疫荧光分析显示，WBM提取物中断AR的核质分布。PSA启动子-荧光素酶活性测定表明，WBM提取物抑制DHT诱导的荧光素酶活性。对WBM处理的LNCaP细胞的RNA-Seq证实，WBM处理抑制雄激素反应途径和细胞周期控制途径。我们的PDX显示，口服WBM提取物（200 mg/kg/天）可抑制肿瘤生长，并降低肿瘤和血清中的PSA水平。在本研究中，我们还通过进行LanthaScreen™ TR-FRET AR共活化剂相互作用试验鉴定了共轭亚油酸异构体（CLA-9 Z11 E）作为强AR拮抗剂。CLA-9 Z11 E的抑制作用（IC 50：350 nM）比已知的AR拮抗剂醋酸环丙孕酮（IC 50：672 nM）强近两倍。从这项研究中获得的信息提高了对WBM如何有助于预防和治疗PCa的整体理解。
White button mushroom (WBM) (Agaricus bisporus) is a potential prostate cancer (PCa) chemopreventative and therapeutic agent. Our clinical phase I trial of WBM powder in patients with biochemically recurrent PCa indicated that WBM intake reduced the circulating levels of prostate-specific antigen (PSA). We hypothesized that WBM exerts its effects on PCa through the androgen receptor (AR) signaling axis. Therefore, we conducted a reverse translational study with androgen-dependent PCa cell lines (LNCaP and VCaP) and patient-derived-xenografts (PDX) from a prostate tumor (TM00298). In both LNCaP and VCaP cells, western blots and qRT-PCR assays indicated that WBM extract (6~30 mg/mL) suppressed DHT-induced PSA expression and cell proliferation in a dose-dependent manner. Immunofluorescence analysis of AR revealed that WBM extract interrupted the AR nuclear-cytoplasmic distribution. PSA promotor-luciferase assay suggested that WBM extract inhibited DHT-induced luciferase activity. RNA-Seq on WBM-treated LNCaP cells confirmed that WBM treatment suppressed the androgen response pathways and cell-cycle control pathways. Our PDX showed that oral intake of WBM extract (200 mg/kg/day) suppressed tumor growth and decreased PSA levels in both tumors and serum. In the present study, we also identified a conjugated linoleic acid isomer (CLA-9Z11E) as a strong AR antagonist by performing LanthaScreen™ TR-FRET AR Coactivator Interaction Assays. The inhibitory effect of CLA-9Z11E (IC50: 350 nM) was nearly two times stronger than the known AR antagonist, cyproterone acetate (IC50: 672 nM). The information gained from this study improves the overall understanding of how WBM may contribute to the prevention and treatment of PCa.
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