Centre National de la Recherche Scientifique, University of Paris Sud,Villejuif, France.
FASEB J. 2012 Jan;26(1):460-7. doi: 10.1096/fj.11-191296. Epub 2011 Oct 7.
Markers of prostate tumor recurrence after radical prostatectomy are lacking and highly demanded. The androgen receptor (AR) is a nuclear receptor that plays a pivotal role in normal and cancerous prostate tissue. AR interacts with a number of proteins modulating its stability, localization, and activity. To test the hypothesis that an increased expression of AR partners might foster tumor development, we immunopurified AR partners in human tumors xenografted into mice. One of the identified AR partners was the multifunctional enzyme carbamoyl-phosphate synthetase II, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the 3 initial steps of pyrimidine biosynthesis. We combined experiments in C4-2, LNCaP, 22RV1, and PC3 human prostate cell lines and analysis of frozen radical prostatectomy samples to study the CAD-AR interaction. We show here that in prostate tumor cells, CAD fosters AR translocation into the nucleus and stimulates its transcriptional activity. Notably, in radical prostatectomy specimens, CAD expression was not correlated with proliferation markers, but a higher CAD mRNA level was associated with local tumor extension (P=0.049) and cancer relapse (P=0.017). These results demonstrate an unsuspected function for a key metabolic enzyme and identify CAD as a potential predictive marker of cancer relapse.
前列腺癌根治术后肿瘤复发的标志物缺乏且需求较高。雄激素受体（AR）是一种核受体，在正常和癌性前列腺组织中发挥关键作用。AR 与许多调节其稳定性、定位和活性的蛋白质相互作用。为了验证 AR 伴侣表达增加可能促进肿瘤发展的假设，我们在异种移植到小鼠中的人肿瘤中免疫纯化了 AR 伴侣。鉴定出的 AR 伴侣之一是多功能酶氨基甲酰磷酸合成酶 II、天冬氨酸转氨甲酰酶和二氢乳清酸酶（CAD），它催化嘧啶生物合成的前 3 个步骤。我们结合了 C4-2、LNCaP、22RV1 和 PC3 人前列腺细胞系的实验以及对根治性前列腺切除术样本的分析，研究了 CAD-AR 相互作用。我们在这里表明，在前列腺肿瘤细胞中，CAD 促进 AR 向核内易位并刺激其转录活性。值得注意的是，在根治性前列腺切除术标本中，CAD 的表达与增殖标志物无关，但较高的 CAD mRNA 水平与局部肿瘤扩展（P=0.049）和癌症复发（P=0.017）相关。这些结果表明一种关键代谢酶具有意想不到的功能，并将 CAD 鉴定为癌症复发的潜在预测标志物。
