Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target.
Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target.
复制标题
DOI：
10.1093/jnci/djv371
复制
发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Neal DE
中科院分区：
文献类型：
--
作者：
Asim M;Massie CE;Orafidiya F;Pértega-Gomes N;Warren AY;Esmaeili M;Selth LA;Zecchini HI;Luko K;Qureshi A;Baridi A;Menon S;Madhu B;Escriu C;Lyons S;Vowler SL;Zecchini VR;Shaw G;Hessenkemper W;Russell R;Mohammed H;Stefanos N;Lynch AG;Grigorenko E;D'Santos C;Taylor C;Lamb A;Sriranjan R;Yang J;Stark R;Dehm SM;Rennie PS;Carroll JS;Griffiths JR;Tavaré S;Mills IG;McEwan IJ;Baniahmad A;Tilley WD;Neal DE
雄激素受体(AR)是前列腺癌(PCa)的主要药物靶点。我们描述了AR调节的动态组，以确定AR信号的临床相关和可用药的效应器。使用全基因组方法，我们询问了所有AR调节的激酶。其中良性病变195例，前列腺上皮内瘤变(PIN)153例，前列腺癌(PCa)病变359例。我们通过生化分析询问了CHKA如何调节AR信号，并研究了雄激素对PCa男性患者CHKA表达的调节，包括未治疗(n=20)和雄激素生物合成抑制剂dearelix治疗(n=27)。我们用RNA测序的方法研究了CHKA抑制对PCA转录组的影响，并检测了抑制CHKA对细胞生长、克隆存活和侵袭的影响。用带有可诱导CHKA基因敲除的基因工程前列腺癌细胞在小鼠体内产生异种移植瘤(每组6例)。数据分析采用χ-2检验、COX回归分析和卡普兰-迈耶方法。所有的统计检验都是双面的。CHKA在细胞系、异种移植瘤和人体组织中的表达受雄激素调节(对数倍数从6.75到6.59，P=0.002)，并与肿瘤分期呈正相关。CHKA直接与AR的配体结合域(LBD)结合，增强其稳定性。因此，CHKA是第一个被确定为AR伴侣的激酶。抑制CHKA抑制AR转录程序，包括丰富的蛋白质折叠调节途径，降低AR蛋白水平，并抑制PCa细胞系、人PCa外植体和肿瘤移植瘤的生长。据我们所知，CHKA可以作为AR分子伴侣，提供了激酶作为分子伴侣的第一个证据，使CHKA既是肿瘤进展的标志，也是PCa潜在的治疗靶点。
The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling. Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ2 tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided. CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts. CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.