和厚朴酚抑制前列腺癌细胞中的雄激素受体活性。
Honokiol inhibits androgen receptor activity in prostate cancer cells.
机构信息
Department of Pharmacology & Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
出版信息
Prostate. 2014 Apr;74(4):408-20. doi: 10.1002/pros.22762. Epub 2013 Dec 11.
BACKGROUND
We have shown previously that honokiol (HNK), a bioactive component of the medicinal plant Magnolia officinalis, inhibits growth of human prostate cancer cells in vitro and in vivo. However, the effect of HNK on androgen receptor (AR) signaling has not been studied.
METHODS
LNCaP, C4-2, and TRAMP-C1 cells were used for various assays. Trypan blue dye exclusion assay or clonogenic assay was performed for determination of cell viability. The effects of HNK and/or its analogs on protein levels of AR and its target gene product prostate specific antigen (PSA) were determined by western blotting. RNA interference of p53 was achieved by transient transfection. Reverse transcription-polymerase chain reaction was performed for mRNA expression of AR. Nuclear level of AR was visualized by microscopy. Apoptosis was quantified by DNA fragmentation assay or flow cytometry after Annexin V-propidium iodide staining.
RESULTS
HNK and its dichloroacetate analog (HDCA) were relatively more effective in suppressing cell viability and AR protein level than honokiol epoxide or biseugenol. Nuclear translocation of AR stimulated by a synthetic androgen (R1881) was markedly suppressed in the presence of HNK. Downregulation of AR protein resulting from HNK exposure was attributable to transcriptional repression as well as proteasomal degradation. HNK-mediated suppression of AR protein was maintained in LNCaP cells after knockdown of p53 protein. HNK-induced apoptosis was not affected by R1881 treatment.
CONCLUSIONS
The present study demonstrates, for the first time, that HNK inhibits activity of AR in prostate cancer cells regardless of the p53 status.
背景
我们之前已经表明，厚朴酚（HNK），一种药用植物厚朴的生物活性成分，在体外和体内抑制人前列腺癌细胞的生长。然而，HNK 对雄激素受体（AR）信号的影响尚未研究。
方法
使用 LNCaP、C4-2 和 TRAMP-C1 细胞进行各种测定。台盼蓝排斥试验或集落形成试验用于测定细胞活力。通过 Western blot 测定 HNK 及其类似物对 AR 及其靶基因产物前列腺特异性抗原（PSA）的蛋白水平的影响。通过瞬时转染实现 p53 的 RNA 干扰。进行逆转录-聚合酶链反应以测定 AR 的 mRNA 表达。通过显微镜观察 AR 的核水平。通过 DNA 片段化测定或 Annexin V-碘化丙啶染色后的流式细胞术定量细胞凋亡。
结果
HNK 及其二氯乙酸酯类似物（HDCA）在抑制细胞活力和 AR 蛋白水平方面比厚朴酚环氧化物或双丁香酚更有效。合成雄激素（R1881）刺激的 AR 核易位在 HNK 存在下明显受到抑制。HNK 暴露导致的 AR 蛋白下调归因于转录抑制和蛋白酶体降解。在敲低 p53 蛋白后，LNCaP 细胞中 HNK 介导的 AR 蛋白抑制得以维持。HNK 诱导的细胞凋亡不受 R1881 处理的影响。
结论
本研究首次表明，HNK 抑制前列腺癌细胞中 AR 的活性，无论 p53 状态如何。
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