A nongenomic mechanism for “metalloestrogenic” effects of cadmium in human uterine leiomyoma cells through G protein-coupled estrogen receptor
Cadmium (Cd) is a ubiquitous environmental metal that is reported to be a “metalloestrogen.” Uterine leiomyomas (fibroids) are estrogen-responsive gynecologic neoplasms that can be the target of xenoestrogens. Previous epidemiology studies have suggested Cd may be associated with fibroids. We have shown that Cd can stimulate proliferation of human uterine leiomyoma (ht-UtLM) cells, but not through classical estrogen receptor (ER) binding. Whether nongenomic ER pathways are involved in Cd-induced proliferation is unknown. In the present study, by evaluating G protein-coupled estrogen receptor (GPER), ERα36, and phospho-epidermal growth factor receptor (EGFR) expression in human tissues, we found that GPER, ERα36 and phospho-EGFR were all highly expressed in fibroids compared to patient-matched myometrial tissues. In ht-UtLM cells, cell proliferation was increased by low doses of Cd (0.1 µM and 10 µM), and this effect could be inhibited by GPER-specific antagonist (G15) pretreatment, or silencing (si) GPER, but not by siERα36. Cd-activated MAPK was dependent on GPER/EGFR transactivation, through significantly increased phospho-Src, matrix metalloproteinase-2 (MMP2) and MMP9, and heparin-binding EGF-like growth factor (HB-EGF) expression/activation. Also, phospho-Src could interact directly to phosphorylate EGFR. Overall, Cd-induced proliferation of human fibroid cells was through a nongenomic GPER/p-src/EGFR/MAPK signaling pathway that did not directly involve ERα36. This suggests that Cd may be a risk factor for uterine fibroids through cross talk between hormone and growth factor receptor pathways.
KeywordsCadmium EGFR Uterine leiomyomas GPER ERα36
The authors sincerely thank Mr. Charles J. Tucker (Fluorescence Microscopy and Imaging Center), NIEHS for helping set up confocal analysis software and Drs. Jerry J. Liu and Wendy Jefferson for their critical review and comments on the manuscript. J.L. thanks the Natural Science Foundation of China (81500613) and Jiangsu Province (BK20150108) for their support. This work was funded by the Intramural Research Program of the NIH, NIEHS and DNTP.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
The collection of human uterine tissues in the present study was in accordance with the approval of Institutional Review Board (IRB) of the NIEHS.
Every patient had signed the informed consent prior to their inclusion in the study.
- Bogusiewicz M, Stryjecka-Zimmer M, Postawski K, Jakimiuk AJ, Rechberger T (2007) Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium. Gynecol Endocrinol 23(9):541–546. https://doi.org/10.1080/09513590701557416 CrossRefPubMedGoogle Scholar
- Gao X, Yu L, Moore AB, Kissling GE, Waalkes MP, Dixon D (2015) Cadmium and proliferation in human uterine leiomyoma cells: evidence of a role for EGFR/MAPK pathways but not classical estrogen receptor pathways. Environ Health Perspect 123(4):331–336. https://doi.org/10.1289/ehp.1408234 CrossRefPubMedGoogle Scholar
- Johnstone EB, Louis GM, Parsons PJ et al (2014) Increased urinary cobalt and whole blood concentrations of cadmium and lead in women with uterine leiomyomata: Findings from the ENDO Study. Reprod Toxicol 49:27–32. https://doi.org/10.1016/j.reprotox.2014.06.007 CrossRefPubMedPubMedCentralGoogle Scholar
- Nakareangrit W, Thiantanawat A, Visitnonthachai D, Watcharasit P, Satayavivad J (2016) Sodium arsenite inhibited genomic estrogen signaling but induced pERalpha (Ser118) via MAPK pathway in breast cancer cells. Environ Toxicol 31(9):1133–1146. https://doi.org/10.1002/tox.22122 CrossRefPubMedGoogle Scholar
- Thornton KJ, Kamange-Sollo E, White ME, Dayton WR (2015) Role of G protein-coupled receptors (GPCR), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), heparin-binding epidermal growth factor-like growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) in trenbolone acetate-stimulated bovine satellite cell proliferation. J Anim Sci 93(9):4291–4301. https://doi.org/10.2527/jas.2015-9191 CrossRefPubMedGoogle Scholar