Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer.
Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer.
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DOI：
10.7554/elife.27159
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发表时间：
2017-08-10
期刊：
影响因子：
7.7
通讯作者：
Brown M
中科院分区：
文献类型：
--
作者：
Cato L;Neeb A;Sharp A;Buzón V;Ficarro SB;Yang L;Muhle-Goll C;Kuznik NC;Riisnaes R;Nava Rodrigues D;Armant O;Gourain V;Adelmant G;Ntim EA;Westerling T;Dolling D;Rescigno P;Figueiredo I;Fauser F;Wu J;Rottenberg JT;Shatkina L;Ester C;Luy B;Puchta H;Troppmair J;Jung N;Bräse S;Strähle U;Marto JA;Nienhaus GU;Al-Lazikani B;Salvatella X;de Bono JS;Cato AC;Brown M
靶向位于雄激素受体（AR）N端的激活功能-1（AF-1）结构域是目前抑制前列腺癌（PCa）中AR作用的方法的有吸引力的治疗替代方案。在这里，我们表明，AR AF-1是由cochaperone袋-1L绑定。AR相互作用结构域中的突变或Bag-1 L的缺失消除了AR信号传导并减少了PCa生长。临床上，Bag-1 L蛋白水平随着去势抵抗性PCa（CRPC）的进展而增加，原发性PCa中高水平的Bag-1 L与这些肿瘤进展时阿比特龙的临床获益减少相关。有趣的是，Bag-1 L中对于其与AR AF-1相互作用重要的残基位于潜在的可药物化口袋内，暗示Bag-1 L是PCa的潜在治疗靶点。前列腺癌是世界上第二大常见的男性癌症。癌症依赖于一种称为雄激素受体的蛋白质来发育和生长。目前，前列腺癌的一些最常见的治疗方法，特别是在其晚期阶段，是阻断这种受体活性的药物。然而，这样的治疗仅在有限的时间段内是成功的，因此仍然需要抑制这种受体的替代方法。雄激素受体必须与许多蛋白质结合才能发挥其活性。这些蛋白质包括一种称为Bag-1 L的蛋白质，它对前列腺癌的发展也很重要。阻止这种蛋白质与雄激素受体结合可能代表了治疗前列腺癌的新方法;但首先重要的是要了解这种相互作用实际上是如何调节受体活性的。现在，卡托等人分析了从43名前列腺癌患者身上收集的癌细胞样本，发现Bag-1 L水平随着疾病的进展而增加。然后查看患者的医疗记录，发现针对雄激素受体的治疗在Bag-1 L水平高的人中效果较差。相反，改变、去除或抑制实验室中生长的前列腺癌细胞中的Bag-1 L会使受体活性降低，使细胞生长缓慢。进一步的实验继续揭示Bag-1 L与雄激素受体的调节区相互作用。卡托等人注意到，这个区域在很大程度上仍未在治疗上进行探索，因为它具有一些独特的结构特性，限制了它与药物分子相互作用的程度。靶向Bag-1 L并阻止其与雄激素受体的该区域结合将代表抑制雄激素受体和治疗前列腺癌患者的不同方法。这些新的发现应该为制药公司提供他们需要立即开始筛选针对Bag-1 L的疗法的大部分信息。最终，卡托等人希望任何后续发现都能通过改善目前可用的治疗方法使前列腺癌患者受益。
Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa. Prostate cancer is the second most common cancer in men around the world. The cancer relies on a protein called the androgen receptor in order to develop and grow. Currently, some of the most common treatments for prostate cancer, especially in its advanced stages, are drugs that block the activity of this receptor. However, such treatments are only successful for a limited period of time, and so alternative methods to inhibit this receptor are still needed. The androgen receptor must bind to a number of proteins to carry out its activity. These proteins include one called Bag-1L, which is also important for the development of prostate cancer. Stopping such a protein from binding with the androgen receptor might represent a new way to treat prostate cancer; but first it will be important to understand how this interaction actually regulates the activity of the receptor. Now, Cato et al. have analyzed samples of cancer cells that had been collected from 43 patients with prostate cancer and found that Bag-1L levels increase as the disease progresses. Looking at the patients’ medical records then revealed that therapies targeting the androgen receptor were less effective in people with high levels of Bag-1L. Conversely, altering, removing or inhibiting Bag-1L in prostate cancer cells grown in the laboratory made the receptor less active and made the cells grow slower. Further experiments went on to reveal that Bag-1L interacts with a regulatory region of the androgen receptor. Cato et al. note that this region remains largely unexplored therapeutically, because it has some unique structural properties that restrict how much it can interact with drug molecules. Targeting Bag-1L and stopping it from binding to this region of the androgen receptor would represent a different approach to inhibiting the androgen receptor and treating patients with prostate cancer. Together these new findings should provide pharmaceutical companies with much of the information they would require to immediately start screening for therapies that target Bag-1L. Ultimately, Cato et al. hope that any follow-up findings will benefit prostate cancer patients by improving the currently available treatments.