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
*Department of Biology, Bellarmine University, Louisville, Kentucky 40205;
†Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky 40292.
Toxicol Sci. 2016 Jul;152(1):62-71. doi: 10.1093/toxsci/kfw064. Epub 2016 Apr 12.
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.
流行病学证据表明，接触镉和砷会增加患肺癌的风险。镉和砷是环境污染物，可通过激活乳腺癌和其他癌细胞系中的雌激素受体（ERs）来充当内分泌干扰物（EDs），但它们在肺癌中作为EDs的活性尚未得到测试。在此，我们研究了氯化镉（CdCl2）和亚砷酸钠（NaAsO2）对人肺腺癌细胞系增殖的影响。结果表明，在环境相关的纳摩尔浓度下，CdCl2和NaAsO2均以与17β-雌二醇（E2）相似的方式刺激H1793、H2073和H1944细胞的增殖，但对H1792或H1299细胞无此作用。对H1793细胞的进一步研究表明，100 nM CdCl2和NaAsO2能迅速刺激丝裂原活化蛋白激酶（MAPK，细胞外信号调节激酶）磷酸化，在15分钟时检测到峰值。抑制剂研究表明，NaAsO2、CdCl2和E2对MAPK的快速磷酸化作用涉及ER、Src、表皮生长因子受体和G蛋白偶联ER（GPER），且通过百日咳毒素敏感途径发挥作用。CdCl2和E2对MAPK的激活作用可能也涉及ERβ。本研究支持膜ER和GPER信号传导参与介导肺腺癌细胞对环境相关纳摩尔浓度的CdCl2和NaAsO2的细胞反应。
