Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest.
Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest.
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DOI：
10.1038/cdd.2010.20
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发表时间：
2010-09
影响因子：
12.4
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中科院分区：
文献类型：
--
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G蛋白偶联受体30（GPR30）具有雌激素结合亲和力，并介导雌激素的非基因组信号传导以调节细胞生长。我们在此首次证明，与所报道的GPR30对乳腺癌和卵巢癌细胞生长的促进作用相反，受体特异性的非雌激素配体G - 1激活GPR30可在体外抑制雄激素依赖性和非依赖性前列腺癌细胞（PCa）的生长，并在体内抑制PC - 3异种移植物的生长。然而，G - 1在完整小鼠的前列腺中未引起生长或组织学变化，并且不抑制静止的BPH - 1（一种永生化的良性前列腺上皮细胞系）的生长。用G - 1处理PC - 3细胞可诱导细胞周期停滞在G2期，并降低PC - 3细胞中G2检查点调节因子（细胞周期蛋白A2、细胞周期蛋白B1、cdc25c和cdc2）的表达以及它们共同的转录调节因子NF - YA的磷酸化。通过在本研究中广泛使用小干扰RNA敲低实验和MEK抑制剂PD98059，我们剖析了G - 1诱导抑制PC - 3细胞生长的潜在机制，该机制是通过GPR30介导的，随后是Erk1/2的持续激活以及p21的c - jun/c - fos依赖性上调，从而导致PC - 3细胞在G2期生长停滞。这一信号通路的发现为未来开发基于GPR30的前列腺癌疗法奠定了基础。
G protein–coupled receptor 30 (GPR30) exhibits estrogen-binding affinity and mediates nongenomic signaling of estrogen to regulate cell growth. We here demonstrated for the first time, in contrast to the reported promoting action of GPR30 on the growth of breast and ovarian cancer cells, that activation of GPR30 by the receptor-specific, non-estrogenic ligand G-1 inhibited growth of androgen-dependent and -independent prostate cancer (PCa) cells in vitro and PC-3 xenografts in vivo. However, G-1 elicited no growth or histological changes in the prostates of intact mice and did not inhibit growth in quiescent BPH-1, an immortalized benign prostatic epithelial cell line. Treatment of PC-3 cells with G-1-induced cell-cycle arrest at the G2 phase and reduced the expression of G2-checkpoint regulators (cyclin A2, cyclin B1, cdc25c, and cdc2) and the phosphorylation of their common transcriptional regulator NF-YA in PC-3 cells. With the extensive use of siRNA knockdown experiments and the MEK inhibitor PD98059 in the present study, we dissected the mechanism underlying G-1–induced inhibition of PC-3 cell growth, which was mediated through GPR30, followed by a sustained activation of Erk1/2 and a c-jun/c-fos-dependent upregulation of p21, resulting in the arrest of PC-3 growth at the G2 phase. The discovery of this signaling pathway lays the foundation for future development of GPR30-based therapies for PCa.
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影响因子：
4.8
作者：
Kardassis, D;Papakosta, P;Moustakas, A
通讯作者：
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影响因子：
5.3
作者：
Dulic, V;Stein, GH;Reed, SI
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Reed, SI
DOI：
10.1016/j.jsbmb.2008.03.006
发表时间：
2008-04-01
影响因子：
4.1
作者：
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通讯作者：
Arterburn, Jeffrey B.
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作者：
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影响因子：
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作者：
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通讯作者：
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