Open Access“Metalloestrogenic” effects of cadmium downstream of G protein-coupled estrogen receptor and mitogen-activated protein kinase pathways in human uterine fibroid cells
Author(s) -
Linda ChiaHui Yu,
Jingli Liu,
Yuchao Yan,
Alanna Burwell,
Lysandra Castro,
Min Shi,
Darlene Dixon
Publication year - 2021
Publication title -
archives of toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.264
H-Index - 111
eISSN - 1432-0738
pISSN - 0340-5761
DOI - 10.1007/s00204-021-03033-z
Subject(s) - cyclin d1 , estrogen receptor , protein kinase a , cyclin b , mapk/erk pathway , cancer research , microbiology and biotechnology , biology , cyclin dependent kinase 2 , cyclin dependent kinase 4 , cyclin d , chemistry , kinase , cell cycle , biochemistry , cell , cancer , breast cancer , genetics
Cadmium (Cd) is a toxic metal reported to act as an estrogen "mimic" in the rat uterus and in vitro. We have reported that Cd stimulates proliferation of estrogen-responsive human uterine leiomyoma (ht-UtLM; fibroid) cells through nongenomic signaling involving the G protein-coupled estrogen receptor (GPER), with activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (pMAPK44/42). In this study, we explored Cd-induced mechanisms downstream of MAPK and whether Cd could stimulate phosphorylation of Histone H3 at serine 10 (H3Ser10ph) through activated Aurora B kinase (pAurora B), a kinase important in activation of histone H3 at serine 10 during mitosis, and if this occurs via Fork head box M1 (FOXM1) and cyclin D1 immediately downstream of MAPK. We found that Cd increased proliferating cell nuclear antigen (PCNA) and H3Ser10ph expression by immunofluorescence, and that H3ser10ph and pAurora B were coexpressed along the metaphase plate in ht-UtLM cells. In addition, Cd-exposed cells showed higher expression of pMAPK44/42, FOXM1, pAurora B, H3ser10ph, and Cyclin D1 by western blotting. Immunoprecipitation and proximity ligation assays further indicated an association between FOXM1 and Cyclin D1 in Cd-exposed cells. These effects were attenuated by MAPK kinase (MEK1/2) inhibitor. In summary, Cd-induced proliferation of ht-UtLM cells occurred through activation of Histone H3 and Aurora B via FOXM1/Cyclin D1 interactions downstream of MAPK. This provides a molecular mechanism of how Cd acts as an "estrogen mimic" resulting in mitosis in hormonally responsive cells.