title: Arsenite and Cadmium Activate MAPK/ERK via Membrane Estrogen Receptors and G-Protein Coupled Estrogen Receptor Signaling in Human Lung Adenocarcinoma Cells.
abstract: 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.
authors.affiliation: *Department of Biology, Bellarmine University, Louisville, Kentucky 40205; mhuff@bellarmine.edu.
authors.forename: Mary O
authors.initials: MO
authors.lastname: Huff
authors.affiliation: *Department of Biology, Bellarmine University, Louisville, Kentucky 40205;
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Todd
authors.affiliation: *Department of Biology, Bellarmine University, Louisville, Kentucky 40205;
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Smith
authors.affiliation: *Department of Biology, Bellarmine University, Louisville, Kentucky 40205;
authors.forename: Julie T
authors.initials: JT
authors.lastname: Elpers
authors.affiliation: *Department of Biology, Bellarmine University, Louisville, Kentucky 40205;
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Smith
authors.affiliation: *Department of Biology, Bellarmine University, Louisville, Kentucky 40205;
authors.forename: Robert D
authors.initials: RD
authors.lastname: Murphy
authors.affiliation: *Department of Biology, Bellarmine University, Louisville, Kentucky 40205;
authors.forename: Allison S
authors.initials: AS
authors.lastname: Bleser-Shartzer
authors.affiliation: *Department of Biology, Bellarmine University, Louisville, Kentucky 40205;
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Hoerter
authors.affiliation: †Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky 40292.
authors.forename: Brandie N
authors.initials: BN
authors.lastname: Radde
authors.affiliation: †Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky 40292.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D018053:Arsenites / Q000633:toxicity*; D019256:Cadmium Chloride / Q000633:toxicity*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018053:Arsenites; C000600034:ESR2 protein, human; D052244:Endocrine Disruptors; D047629:Estrogen Receptor beta; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D017670:Sodium Compounds; C017947:sodium arsenite; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019256:Cadmium Chloride
keywords: ERK1/2; GPER; MAPK; arsenic; arsenite; cadmium; endocrine disruptor; estrogen receptor; lung cancer