'Metalloestrogenic' effects of cadmium downstream of G protein-coupled estrogen receptor and mitogen-activated protein kinase pathways in human uterine fibroid cells
| Autor: | Yitang Yan, Alanna Burwell, Jingli Liu, Lysandra Castro, Min Shi, Darlene Dixon, Linda Yu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Health Toxicology and Mutagenesis Aurora B kinase Mitosis Estrogen receptor H3Ser10ph Toxicology Receptors G-Protein-Coupled Histones 03 medical and health sciences Histone H3 0302 clinical medicine Cyclin D1 Aurora Kinase B Humans Inorganic Compounds Aurora B Fibroid cells Protein kinase A Cells Cultured Cell Proliferation Leiomyoma biology Chemistry Forkhead Box Protein M1 FOXM1 General Medicine Cell biology 030104 developmental biology Receptors Estrogen 030220 oncology & carcinogenesis Mitogen-activated protein kinase Uterine Neoplasms biology.protein Female Mitogen-Activated Protein Kinases GPER Cadmium Signal Transduction |
| Zdroj: | Archives of Toxicology |
| ISSN: | 1432-0738 0340-5761 |
| DOI: | 10.1007/s00204-021-03033-z |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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