G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth.
G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth.
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DOI：
10.1155/2013/472720
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发表时间：
2013
影响因子：
1.9
通讯作者：
Prossnitz ER
中科院分区：
文献类型：
--
作者：
Petrie WK;Dennis MK;Hu C;Dai D;Arterburn JB;Smith HO;Hathaway HJ;Prossnitz ER
子宫内膜癌是女性生殖道最常见的癌症。GPER/GPR30是一种跨膜的G蛋白偶联受体，是继ERα和ERβ之后的第三种雌激素受体。GPER的高表达预示着子宫内膜癌和卵巢癌的生存不良，但尽管如此，涉及子宫内膜癌的雌激素介导的信号通路和特异性雌激素受体仍不清楚。在这里，利用ERα阴性的HEC50子宫内膜癌细胞，我们证明GPER通过基质金属蛋白酶的激活和随后的EGFR的反式激活来介导雌激素刺激的ERK和PI3K的激活，ER靶向治疗药物(4-羟基他莫昔芬、ICI182,780/fulvestrant和雷洛昔芬)、植物雌激素金雀异黄素和“ERα选择性”激动剂丙基吡唑三醇也作为Gper激动剂发挥作用。此外，Hec50细胞的异种移植瘤在G-1和雌激素的促进下生长，后者被GPER选择性的G36药物拮抗所抑制。这些结果对于推定的ER选择性配体的使用，特别是对于“ER靶向”疗法的广泛长期使用具有重要的意义。此外，我们的发现揭示了许多临床研究中报道的SERM/SERD副作用的潜在机制。最后，我们的结果首次证明了体内药物抑制GPER活性可以阻止雌激素介导的肿瘤生长。
Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.