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

[[abstract]]Estrogen and secondhand smoke are key risk factors for nonsmoking female lung cancer patients, who frequently have lung adenocarcinoma and show tumor ERalpha expression. We speculated that estrogen and secondhand smoke might cause harmful effects via ERalpha signaling. Our results showed that 17beta-estradiol (E2), the primary form of endogenous estrogen, exacerbated proliferation, migration, and granzyme B resistance of lung adenocarcinoma cells in an ERalpha-dependent manner. Cigarette sidestream smoke particulate matter (CSSP), the major component of secondhand smoke, could activate ERalpha activity dose dependently in human lung adenocarcinoma cells. The estrogenic activity of CSSP was abolished by an ERalpha-selective antagonist. CSSP regulated the nuclear entry, phosphorylation, and turnover of ERalpha similarly to E2. Furthermore, CSSP enhanced E2-stimulated ERalpha activity and Ser118 phosphorylation even when ERalpha became saturated with E2. Activation of ERalpha by CSSP required GSK3beta activity, but not involving polycyclic aromatic hydrocarbons, reactive oxygen species, calcium, epidermal growth factor receptor, and PI3K/Akt. Although CSSP possessed cytotoxicity, ERalpha-expressing cells grew and migrated faster than nonexpressing cells upon recovery from CSSP exposure as observed in E2-pretreated cells. Knockdown of ERalpha by siRNA diminished E2- and CSSP-stimulated cell migration. 21 genes, including SERPINB9, were identified to be upregulated by both E2 and CSSP via ERalpha. Increased SERPINB9 expression was accompanied with increased resistance to granzyme B-mediated apoptosis. This study demonstrates that estrogen has ERalpha-dependent tumor-promoting activity. CSSP acts like estrogen and shows a potential to enhance estrogen-induced ERalpha action