Abstract 1332: Cigarette smoking attenuates TGF-β-mediated tumor suppression function through down-regulation of Smad3 in lung cancer

Abstract Cigarette smoking has been connected to an array of chronic lung diseases and one of the major causes of morbidity and mortality. Epidemiological studies have demonstrated the most cases of lung cancers (85-90%) are directly attributable to tobacco smoking. Although much information is gained about the effect of cigarette smoking on various signaling pathways causing lung cancer, no information is available about the effect cigarette smoking on the TGF-β-dependent initiation and progression of lung cancer. To address this issue, A549, a lung adenocarcinma cell line and HPL1A, an immortalized lung epithelial cell line were chronically treated with cigarette smoke condensate (CSC) to mimic the conditions of long-term cigarette smoking. Prolonged exposure of these cells to CSC resulted in a decrease in Smad3 and Smad4 complex formation and TGF-ß-mediated transcription due to reduced expression of Smad3. As a consequence, the cells were less apoptotic, were more viable, and lost TGF-β mediated growth inhibition. We found that the decrease in apoptosis is due to the up-regulation of Bcl2, which is a downstream target of Smad3. The repression of Smad3 expression is at the promoter level and is due to histone deacetylation. Withdrawal of CSC treatment resulted in the restoration of Smad3 expression, reduction in cell viability and increased TGF-β mediated growth inhibition. Rescue experiment with reintroduction of Smad3 in the 300 day CSC treated cells restored TGF-β signaling, increased apoptosis and decreased cell viability. Finally, three hundred days CSC exposure dramatically increased the tumorigenicity of cells in vivo, and Smad3 re-expression reverses this effect. In patient samples, there is a trend that expression of Smad3 goes down in smokers compared to non-smokers. Collectively, these data provide evidence that cigarette smoking promotes tumorigenicity partly by abrogating TGF-β mediated growth inhibition and apoptosis by reducing expression of Smad3. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1332. doi:10.1158/1538-7445.AM2011-1332