Arsenite and Cadmium Activate MAPK/ERK via Membrane Estrogen Receptors and G-Protein Coupled Estrogen Receptor Signaling in Human Lung Adenocarcinoma Cells

• Published in: Toxicological sciences Vol. 152; no. 1; pp. 62 - 71
• Main Authors: Huff, Mary O, Todd, Sarah L, Smith, Aaron L, Elpers, Julie T, Smith, Alexander P, Murphy, Robert D, Bleser-Shartzer, Allison S, Hoerter, Jacob E, Radde, Brandie N, Klinge, Carolyn M
• Format: Journal Article
• Language: English
• Published: United States 01.07.2016
• Subjects: Adenocarcinoma - enzymology; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Arsenites - toxicity; Cadmium Chloride - toxicity; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Endocrine Disruptors - toxicity; Enzyme Activation; ErbB Receptors - metabolism; Estrogen Receptor beta - agonists; Estrogen Receptor beta - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Humans; Lung Neoplasms - enzymology; Lung Neoplasms - pathology; Phosphorylation; Receptors, Estrogen - metabolism; Receptors, G-Protein-Coupled - metabolism; Signal Transduction - drug effects; Sodium Compounds - toxicity; src-Family Kinases - metabolism; Time Factors; lung cancer; ERK1/2; estrogen receptor; GPER; arsenite; cadmium; endocrine disruptor; MAPK; arsenic
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfw064

Epidemiological evidence indicates that cadmium and arsenic exposure increase lung cancer risk. Cadmium and arsenic are environmental contaminants that act as endocrine disruptors (EDs) by activating estrogen receptors (ERs) in breast and other cancer cell lines but their activity as EDs in lung cancer is untested. Here, we examined the effect of cadmium chloride (CdCl2) and sodium arsenite (NaAsO2) on the proliferation of human lung adenocarcinoma cell lines. Results demonstrated that both CdCl2 and NaAsO2 stimulated cell proliferation at environmentally relevant nM concentrations in a similar manner to 17β-estradiol (E2) in H1793, H2073, and H1944 cells but not in H1792 or H1299 cells. Further studies in H1793 cells showed that 100 nM CdCl2 and NaAsO2 rapidly stimulated mitogen-activated protein kinase (MAPK, extracellular-signal-regulated kinases) phosphorylation with a peak detected at 15 min. Inhibitor studies suggest that rapid MAPK phosphorylation by NaAsO2, CdCl2, and E2 involves ER, Src, epidermal growth factor receptor, and G-protein coupled ER (GPER) in a pertussis toxin-sensitive pathway. CdCl2 and E2 activation of MAPK may also involve ERβ. This study supports the involvement of membrane ER and GPER signaling in mediating cellular responses to environmentally relevant nM concentrations of CdCl2 and NaAsO2 in lung adenocarcinoma cells.