Molecular Carcinogenesis, 2013, 52(9):715-25.

Endocrine Disrupting Chemicals Promote the Growth of Ovarian Cancer Cells via the ER-CXCL12-CXCR4 Signaling Axis

Julie M. Hall, Kenneth S. Korach

College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC 27506, USA.

The majority of ovarian cancers over-express the estrogen receptor (ERα) and grow in response to estrogens. We previously demonstrated that ER induction of the chemokine CXCL12 (stromal cell-derived factor-1) is required for estradiol (E2)-stimulated proliferation of human ovarian carcinoma cells. In the current study, we report that known "endocrine disrupting chemicals" (EDCs) display mitogenic activities in ovarian cancer cells via their ability to activate the ER and upregulate CXCL12 expression. Notably, the EDCs genistein, bisphenol A and HPTE stimulated both cell proliferation and induction of CXCL12 mRNA and protein in a manner comparable to estradiol. The effects were completely attenuated by the ER antagonist ICI 182,780, revealing that observed activities of these agents were receptor-mediated. In cell proliferation assays, the mitogenic effects of estradiol and EDCs were obviated by siRNAs targeting CXCL12 and restored upon addition of exogenous CXCL12. Furthermore, an inhibitor to the CXCL12 receptor CXCR4 completely attenuated growth-stimulatory effects of E2 and EDCs. These studies highlight a potential role of EDCs possessing estrogenic activities in the etiology of ovarian cancer. Moreover, they suggest that the ER-CXCL12-CXCR4 signaling axis may represent a promising target for development of therapeutics for ER+ ovarian cancers.

美国《分子癌变》，2012年9月

环境内分泌激素通过 ER-CXCL12- CXCR4 信号通道干扰了化学促进卵巢癌的细胞生长

朱莉 M 霍尔，肯尼斯 S. 科尔施

美国坎贝尔大学药物和健康科学学院

卵巢癌绝大多数过度表达雌激素受体 （e α） 并在对雌激素的响应中成长。先前我们表明了雌二醇 (E2)-刺激人类卵巢癌细胞增殖需要趋化因子 CXCL12 (基质细胞衍生因子-1) 的ER 诱导。在当前的研究中，我们报道了，已知的"内分泌扰乱化学物质"(EDCs) 在卵巢癌细胞中通过激活 ER 并上调 CXCL12 的表达表现出有丝分裂活性。值得注意的是，环境内分泌干扰物金雀异黄素，双酚 A 和HPTE以媲美雌二醇的方式刺激细胞增殖并诱导 CXCL12 的mRNA 和蛋白。ER 拮抗剂ICI 182,780完全衰减了这些作用，揭示了这些试剂的观测活性由受体介导。在细胞增殖试剂中，雌二醇和内分泌干扰物的有丝分裂作用被siRNA 靶向CXCL12去除并通过外源性 CXCL12还原后。此外，一种抑制 CXCL12 受体 的CXCR4 完全衰减了 E2 和内分泌干扰物的生长刺激作用。这些研究强调了具有雌激素活性的环境内分泌干扰物在卵巢癌病理学中的潜在作用。此外，他们认为 ER-CXCL12-CXCR4 信号通道可能代表了ER + 卵巢癌的潜在治疗靶点。