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中国科学家发现治疗前列腺癌新靶点 国际关注Altmetric 81分

已有 2012 次阅读 2016-4-6 09:31 |个人分类:科学计量|系统分类:科研笔记

科学家发现治疗前列腺癌新靶点

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ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. 百度翻译

Wang J . Zou JX . Xue X . Cai D . Zhang Y . Duan Z . Xiang Q . Yang JC . Louie MC . Borowsky AD . Gao AC . Evans CP . Lam KS . Xu J . Kung HJ . Evans RM . Xu Y . Chen HW .
来源: Nat Med ( P 1078-8956 E 1546-170X ) IF:27.363 H指数:357 年: 2016
PMID: 27019329 [Pubmed] 生化与分子生物学,1区

The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.

科学家发现治疗前列腺癌新靶点

本报讯(记者朱汉斌 通讯员黄博纯)中科院广州生物医药与健康研究院许永课题组与美国加州大学陈宏武课题组合作,发现了治疗前列腺癌的新靶点。该研究发现,孤儿核受体RORγ在转移去势抵抗性前列腺癌中高表达,同时RORγ调控雄激素受体AR的表达。采用理论模拟与设计获得的RORγ小分子拮抗剂,能有效抑制AR的基因和蛋白表达水平。因此,RORγ可作为前列腺癌的重要治疗靶点,发展RORγ拮抗剂则将成为治疗前列腺癌的新策略。相关成果日前在线发表于《自然—医学》杂志。

近年来,晚期前列腺癌特别是转移性去势抵抗性前列腺癌的治疗得到迅速发展。而核激素受体成员中的雄激素受体AR,是前列腺癌的关键治疗靶点。

该研究发现,除AR外,核受体成员RORγ对转移性前列腺癌的进展也起到关键作用。RORγ在转移性肿瘤中高表达,而且表达水平与肿瘤转移程度密切相关。研究团队采用基于结构的药物设计方法,获得RORγ的拮抗剂XY011和XY018。后两者通过抑制RORγ,有效阻止AR基因和蛋白表达水平,从而抑制肿瘤生长。

相关专家表示,该研究不仅提供了全新的抗肿瘤靶点,同时提供了重要的先导化合物,为去势抵抗性前列腺癌的治疗提供了重要途径。

《中国科学报》 (2016-04-06 第1版 要闻)

http://news.sciencenet.cn/htmlnews/2016/4/342433.shtm

 



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