title: Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis.
abstract: 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.
authors.affiliation: College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC 27506, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Hall
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D052244:Endocrine Disruptors / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D052244:Endocrine Disruptors; D019718:Receptors, CXCR4; D011960:Receptors, Estrogen; D004958:Estradiol