Cao X, Qin J, Xie Y, Khan O, Dowd F, Scofield M, Lin M-F, Tu Y
Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA.
Oncogene. 2006 Jun 22;25(26):3719-34. doi: 10.1038/sj.onc.1209408. Epub 2006 Jan 30.
Hormones acting through G protein-coupled receptors (GPCRs) can cause androgen-independent activation of androgen receptor (AR) in prostate cancer cells. Regulators of G-protein signaling (RGS) proteins, through their GTPase activating protein (GAP) activities, inhibit GPCR-mediated signaling by inactivating G proteins. Here, we identified RGS2 as a gene specifically downregulated in androgen-independent prostate cancer cells. Expression of RGS2, but not other RGS proteins, abolished androgen-independent AR activity in androgen-independent LNCaP cells and CWR22Rv1 cells. In LNCaP cells, RGS2 inhibited G(q)-coupled GPCR signaling. Expression of exogenous wild-type RGS2, but not its GAP-deficient mutant, significantly reduced AR activation by constitutively activated G(q)Q209L mutant whereas silencing endogenous RGS2 by siRNA enhanced G(q)Q209L-stimulated AR activity. RGS2 had no effect on RGS-insensitive G(q)Q209L/G188S-induced AR activation. Furthermore, extracellular signal-regulated kinase 1/2 (ERK1/2) was found to be involved in RGS2-mediated regulation of androgen-independent AR activity. In addition, RGS2 functioned as a growth suppressor for androgen-independent LNCaP cells whereas androgen-sensitive LNCaP cells with RGS2 silencing had a growth advantage under steroid-reduced conditions. Finally, RGS2 expression level was significantly decreased in human prostate tumor specimens. Taken together, our results suggest RGS2 as a novel regulator of AR signaling and its repression may be an important step during prostate tumorigenesis and progression.
通过G蛋白偶联受体（GPCR）发挥作用的激素可导致前列腺癌细胞中雄激素受体（AR）的非雄激素依赖性激活。G蛋白信号调节（RGS）蛋白通过其GTP酶激活蛋白（GAP）活性，使G蛋白失活来抑制GPCR介导的信号传导。在此，我们鉴定出RGS2是在非雄激素依赖性前列腺癌细胞中特异性下调的基因。RGS2而非其他RGS蛋白的表达，消除了非雄激素依赖性LNCaP细胞和CWR22Rv1细胞中的非雄激素依赖性AR活性。在LNCaP细胞中，RGS2抑制G（q）偶联的GPCR信号传导。外源性野生型RGS2而非其GAP缺陷型突变体的表达，显著降低了组成型激活的G（q）Q209L突变体对AR的激活作用，而通过小干扰RNA（siRNA）沉默内源性RGS2则增强了G（q）Q209L刺激的AR活性。RGS2对RGS不敏感的G（q）Q209L/G188S诱导的AR激活没有影响。此外，发现细胞外信号调节激酶1/2（ERK1/2）参与RGS2介导的非雄激素依赖性AR活性调节。另外，RGS2对非雄激素依赖性LNCaP细胞起生长抑制作用，而沉默RGS2的雄激素敏感LNCaP细胞在类固醇减少的条件下具有生长优势。最后，在人前列腺肿瘤标本中RGS2表达水平显著降低。综上所述，我们的结果表明RGS2是AR信号传导的新型调节因子，其抑制可能是前列腺肿瘤发生和进展过程中的重要步骤。
