Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation.
Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation.
复制标题
DOI：
10.1371/journal.pone.0063563
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Alumkal J
中科院分区：
文献类型：
--
作者：
Gao L;Schwartzman J;Gibbs A;Lisac R;Kleinschmidt R;Wilmot B;Bottomly D;Coleman I;Nelson P;McWeeney S;Alumkal J
雄激素受体（AR）是前列腺癌的主要治疗靶点。在过去的70年里，雄激素剥夺治疗（ADT）一直是主要的治疗焦点。然而，有些患者并没有受益，那些最初对ADT有反应的肿瘤最终会进展。这种作用的一种最近描述的机制是AR的生长和存活促进作用，其独立于AR配体、睾酮和二氢睾酮而发挥。然而，解释这种效应的特异性配体非依赖性AR靶基因尚未得到很好的表征。我们在这里表明，c-Myc是配体非依赖性前列腺癌生长的关键介质，是一个关键的配体非依赖性AR靶基因。使用微阵列分析，我们发现c-Myc和AR表达水平在来自去势抵抗性前列腺癌（CRPC）患者的肿瘤中彼此强烈相关，尽管ADT仍在进展。我们证实了AR以配体非依赖性方式直接调节c-Myc转录，AR和c-Myc抑制减少配体非依赖性前列腺癌细胞生长，并且c-Myc的异位表达减弱了AR抑制的抗生长作用。重要的是，用布罗莫结构域抑制剂JQ 1治疗抑制了c-Myc功能并抑制了配体非依赖性前列腺癌细胞存活。我们的研究结果定义了前列腺癌中两种关键蛋白质- AR和c-Myc -之间的新联系，并证明了AR和c-Myc定向治疗改善前列腺癌控制的潜力。
The androgen receptor (AR) is the principal therapeutic target in prostate cancer. For the past 70 years, androgen deprivation therapy (ADT) has been the major therapeutic focus. However, some patients do not benefit, and those tumors that do initially respond to ADT eventually progress. One recently described mechanism of such an effect is growth and survival-promoting effects of the AR that are exerted independently of the AR ligands, testosterone and dihydrotestosterone. However, specific ligand-independent AR target genes that account for this effect were not well characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer growth, is a key ligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-growth effects of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer – AR and c-Myc – and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control.
登录
查看更多内容
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
5.8
作者：
Mecham, Brigham H.;Nelson, Peter S.;Storey, John D.
通讯作者：
Storey, John D.
影响因子：
45.3
作者：
Efstathiou, Eleni;Titus, Mark;Logothetis, Christopher J.
通讯作者：
Logothetis, Christopher J.
影响因子：
4.8
作者：
Hawksworth, D.;Ravindranath, L.;Petrovics, G.
通讯作者：
Petrovics, G.
DOI：
10.1073/pnas.150006697
发表时间：
2000-08-15
影响因子：
11.1
作者：
Claassen, GF;Hann, SR
通讯作者：
Hann, SR