Kava components down-regulate expression of AR and AR splice variants and reduce growth in patient-derived prostate cancer xenografts in mice.
Kava components down-regulate expression of AR and AR splice variants and reduce growth in patient-derived prostate cancer xenografts in mice.
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DOI：
10.1371/journal.pone.0031213
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zi X
中科院分区：
文献类型：
--
作者：
Li X;Liu Z;Xu X;Blair CA;Sun Z;Xie J;Lilly MB;Zi X
居住在斐济且饮用卡瓦的男性前列腺癌 (PCa) 的发病率较低。然而，移居澳大利亚的斐济男性前列腺癌发病率增加了 5.1 倍。因此，我们研究了卡瓦根提取物及其活性成分（卡瓦内酯和黄酮卡因）对 PCa 生长和雄激素受体 (AR) 表达的潜在影响。具有不同 AR 表达的 PCa 细胞系（LNCaP、LAPC-4、22Rv1、C4-2B、DU145 和 PC-3）以及转化的前列腺肌成纤维细胞系（WPMY-1）用商业卡瓦提取物、卡瓦内酯（卡瓦因、5'6'-脱氢卡瓦因、仰光素、美西斯丁）和黄卡瓦素 B 处理。 AR 及其靶基因的表达（PSA 和 TMPRSS2）进行了检查。将高级别 PCa 标本植入裸鼠体内，将肿瘤碎片通过裸鼠皮下注射，建立两种新型患者来源 PCa 异种移植模型，然后用卡瓦提取物和黄素卡因 B 处理，以检测其对肿瘤生长、AR 表达和血清 PSA 水平的影响。卡瓦提取物和黄卡因 B 有效下调全长 AR 和 AR 剪接变体的表达。卡瓦提取物和卡瓦内酯加速 AR 蛋白降解，而黄卡瓦素 B 通过降低 Sp1 表达以及 Sp1 与 AR 启动子的结合来抑制 AR mRNA 转录。卡瓦根提取物和黄卡因 B 可减少肿瘤生长、肿瘤组织中的 AR 表达以及患者来源的 PCa 异种移植模型中的血清 PSA 水平。这些结果表明，安全的卡瓦产品或其活性成分对于通过靶向 AR 来预防和治疗晚期 PCa 具有潜在的用途。
Men living in Fiji and drinking kava have low incidence of prostate cancer (PCa). However, the PCa incidence among Fijian men who had migrated to Australia, increased by 5.1-fold. We therefore examined the potential effects of kava root extracts and its active components (kavalactones and flavokawains) on PCa growth and androgen receptor (AR) expression. PCa cell lines (LNCaP, LAPC-4, 22Rv1, C4-2B, DU145 and PC-3) with different AR expression, and a transformed prostate myofibroblast cell line (WPMY-1), were treated with a commercial kava extract, kavalactones (kawain, 5′6′-dehydrokawain, yangonin, methysticin) and flavokawain B. Expression of AR and its target genes (PSA and TMPRSS2) was examined. Two novel patient-derived PCa xenograft models from high grade PCa specimens were established by implanting the specimens into nude mice and passing tumor pieces through subcutaneous injection in nude mice, and then treated with kava extract and flavokawain B to examine their effects on tumor growth, AR expression and serum PSA levels. The kava extract and flavokawain B effectively down-regulated the expression of both the full-length AR and AR splice variants. The kava extract and kavalactones accelerated AR protein degradation, while flavokawain B inhibited AR mRNA transcription via decreasing Sp1 expression and the binding of Sp1 to the AR promoter. The kava root extract and flavokawain B reduce tumor growth, AR expression in tumor tissues and levels of serum PSA in the patient-derived PCa xenograft models. These results suggest a potential usefulness of a safe kava product or its active components for prevention and treatment of advanced PCa by targeting AR.
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影响因子：
3.9
作者：
Sharifi N;Gulley JL;Dahut WL
通讯作者：
Dahut WL
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
11.2
作者：
Zi, XL;Simoneau, AR
通讯作者：
Simoneau, AR
影响因子：
168.9
作者：
Scher, Howard I.;Beer, Tomasz M.;Higano, Celestia S.;Anand, Aseem;Taplin, Mary-Ellen;Efstathiou, Eleni;Rathkopf, Dana;Shelkey, Julia;Yu, Evan Y.;Alumkal, Joshi;Hung, David;Hirmand, Mohammad;Seely, Lynn;Morris, Michael J.;Danila, Daniel C.;Humm, John;Larson, Steve;Fleisher, Martin;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
50.3
作者：
Andersen, Raymond J.;Mawji, Nasrin R.;Sadar, Marianne D.
通讯作者：
Sadar, Marianne D.