Abstract 819: Chronic smoking increases tumorigenicity and imparts resistance to platinum-based chemotherapy partly by down-regulating Smad3 in non-small cell lung cancer
Authors: Samanta Debangshu , Datta Pran K. 
Published: August 2012

Abstract
Inactivating mutations in TGF-β receptors and Smad signal transducers that contribute to resistance to TGF-β, are associated with only very small number of NSCLC. The Smad3/Smad4 pathway is important for TGF-β-induced tumor suppressor functions like growth inhibition and apoptosis in normal epithelium and in the early stages of tumor progression. Epidemiological studies have demonstrated that most cases of lung cancers (85-90%) are directly attributable to cigarette smoking. However, nothing is known how smoking is involved in inhibiting tumor suppressor functions of TGF-ß and whether or how the TGF-β signaling proteins might be involved in the chemo resistance of platinum-based drugs in smokers. To address this issue, lung adenocarcinoma A549 and immortalized bronchial epithelial HPL1A cells were chronically treated (300 days) with cigarette smoke condensate (CSC) and dimethyl sulphoxide, as a control to mimic the conditions of long-term cigarette smoking. Prolonged exposure of these cells to CSC resulted in a decreased Smad-mediated TGF-β- signaling due to reduced expression of Smad3 through histone deacetylation. Long-term CSC treatment reduced apoptosis, increased cell viability; decreased TGF-β-mediated growth inhibition, and enhanced tumorigenicity both in vitro and in vivo. Re-expression of Smad3 in the long- term CSC treated cells reversed the cancerous phenotypes observed due to long- term CSC treatment. Immunohistochemical staining of tissue microarrays revealed that Smad3 expression is lower in smokers compared to non-smokers. This is supported by the results from public databases. However, low expression of Smad3 is not a prognostic biomarker to predict the survival outcome of patients with lung cancer. The long long-term CSC treatment also rendered the cells resistant to platinum-based chemotherapy by up-regulating Bcl2. Blocking the effect of Bcl2 both by small molecule inhibitor ABT-737 and siRNA approaches re-sensitized the cells to platinum-based chemotherapy. The re-expression of exogenous Smad3 in the long long-term CSC treated cells decreased the Bcl2 levels and re-sensitized the cells to platinum-based chemotherapy. Thus, down regulation of Smad3 by smoking conditions increases the expression of Bcl2 resulting in the resistance to platinum- based drugs in our model system. Collectively, these data provide evidence that cigarette smoking promotes tumorigenicity and makes the cells resistant to platinum-based chemotherapy by abrogating apoptosis, partly by reducing the expression of Smad3. In the current era of personalized medicine, there is a pressing need to identify predictive biomarkers for stratifying smokers to predict the response to contemporary platinum-based chemotherapy. The low expression of Smad3 can be a putative predictive biomarker of smokers for platinum-based chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 819. doi:1538-7445.AM2012-819