Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, China.
Eur J Pharmacol. 2012 Jun 5;684(1-3):27-35. doi: 10.1016/j.ejphar.2012.03.034. Epub 2012 Apr 2.
The presence of corticotropin-releasing hormone (CRH) in breast cancer biopsies suggests that it may play a role in the development of breast cancer. Here, the role of CRH in apoptosis and the relevant mechanisms were investigated. The CRH homologues, Urocortins, which have equal affinity for both corticotropin-releasing hormone receptor types 1 and 2, were secreted in MCF-7 breast cancer cells. CRH (receptor type 1 agonist) and Urocortin2 (receptor type 2 agonist) were used to substitute Urocortin to identify the differences between the two receptors. The results showed that both CRH and Urocortin2 promoted apoptosis of MCF-7 cells by regulating expressions and distributions of androgen receptor and vitamin D receptor. CRH down-regulated androgen receptor mRNA through inducing its decay while up-regulating androgen receptor protein expression and promoting nuclear transportation. Urocortin2 repressed the mRNA production of androgen receptor but had no significant impact on its protein expression. Both CRH and Urocortin2 time-dependently increased the protein expression of vitamin D receptor which translocated into the nuclei to realize its genic activity thereafter. The activity of CRH and Urocortin2 could be inhibited by Antalarmin and Antisauvagine-30, respectively. Additional analyses showed that CRH and Urocortin2 both phosphorylated heat shock protein 27, and this phosphorylation was associated with the nuclear transportation of vitamin D receptor. In conclusion, the results firstly revealed that CRH and Urocortin2 could induce breast cancer cell apoptosis via the two different receptors. The mechanisms involve phosphorylation of heat shock protein 27, the increment of androgen receptor and vitamin D receptor protein expression and their nuclear translocation.
促肾上腺皮质激素释放激素（CRH）存在于乳腺癌活检中，表明其可能在乳腺癌的发生中发挥作用。在此，研究了 CRH 在细胞凋亡中的作用及其相关机制。CRH 的同源物，Urocortin，对促皮质素释放激素受体 1 型和 2 型具有同等亲和力，在 MCF-7 乳腺癌细胞中分泌。CRH（受体 1 型激动剂）和 Urocortin2（受体 2 型激动剂）被用来替代 Urocortin，以确定两种受体之间的差异。结果表明，CRH 和 Urocortin2 均可通过调节雄激素受体和维生素 D 受体的表达和分布促进 MCF-7 细胞凋亡。CRH 通过诱导其降解而下调雄激素受体 mRNA，同时上调雄激素受体蛋白表达并促进核转运。Urocortin2 抑制雄激素受体的 mRNA 产生，但对其蛋白表达无明显影响。CRH 和 Urocortin2 均可时间依赖性增加维生素 D 受体的蛋白表达，使其转位入核，从而实现其基因活性。Antalarmin 和 Antisauvagine-30 可分别抑制 CRH 和 Urocortin2 的活性。进一步分析表明，CRH 和 Urocortin2 均可使热休克蛋白 27 磷酸化，且这种磷酸化与维生素 D 受体的核转运有关。综上所述，该研究结果首次揭示了 CRH 和 Urocortin2 可通过两种不同的受体诱导乳腺癌细胞凋亡。其机制涉及热休克蛋白 27 的磷酸化、雄激素受体和维生素 D 受体蛋白表达的增加及其核转位。
