Estrogen and cigarette sidestream smoke particulate matter exhibit ERα-dependent tumor-promoting effects in lung adenocarcinoma cells

Am J Physiol Lung Cell Mol Physiol. 2017 Sep 1;313(3):L477-L490. doi: 10.1152/ajplung.00322.2016. Epub 2017 May 18.

Abstract

Estrogen and secondhand smoke are key risk factors for nonsmoking female lung cancer patients who frequently have lung adenocarcinoma and show tumor estrogen receptor α (ERα) expression. We speculated that estrogen and secondhand smoke might cause harmful effects via ERα signaling. Our results showed that 17β-estradiol (E2), the primary form of endogenous estrogen, exacerbated proliferation, migration, and granzyme B resistance of lung adenocarcinoma cells in an ERα-dependent manner. Cigarette sidestream smoke particulate matter (CSSP), the major component of secondhand smoke, could activate ERα activity dose dependently in human lung adenocarcinoma cells. The estrogenic activity of CSSP was abolished by an ERα-selective antagonist. CSSP regulated the nuclear entry, phosphorylation, and turnover of ERα similarly to E2. Furthermore, CSSP enhanced E2-stimulated ERα activity and Ser118 phosphorylation even when ERα became saturated with E2. Activation of ERα by CSSP required GSK3β activity, but not involving polycyclic aromatic hydrocarbons, reactive oxygen species, calcium, epidermal growth factor receptor, and PI3K/Akt. Although CSSP possessed cytotoxicity, ERα-expressing cells grew and migrated faster than nonexpressing cells on recovery from CSSP exposure as observed in E2-pretreated cells. Knockdown of ERα by siRNA diminished E2- and CSSP-stimulated cell migration. Twenty-one genes, including SERPINB9, were identified to be upregulated by both E2 and CSSP via ERα. Increased SERPINB9 expression was accompanied with increased resistance to granzyme B-mediated apoptosis. This study demonstrates that estrogen has ERα-dependent tumor-promoting activity. CSSP acts like estrogen and shows a potential to enhance estrogen-induced ERα action.

Keywords: ERα; GSK3β; lung adenocarcinoma; polycyclic aromatic hydrocarbons; secondhand smoke.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology*
  • Adenocarcinoma of Lung
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • ErbB Receptors / metabolism
  • Estradiol / toxicity*
  • Estrogen Receptor alpha / metabolism*
  • Gene Expression Profiling
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Granzymes / metabolism
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology*
  • Particulate Matter / toxicity*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein Stability / drug effects
  • Protein Transport / drug effects
  • Proteolysis / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Serpins / metabolism
  • Smoking / adverse effects*
  • Subcellular Fractions / metabolism
  • Transcription, Genetic / drug effects

Substances

  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Particulate Matter
  • Reactive Oxygen Species
  • SERPINB9 protein, human
  • Serpins
  • Estradiol
  • ErbB Receptors
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Granzymes