Inactivating mutations in TGF-©¬ receptors and Smad signal transducers that contribute to resistance to TGF-©¬, are associated with only very small number of NSCLC. The Smad dependent pathway is involved in the tumor suppressive functions of TGF-¥â. Epidemiological studies have demonstrated that most cases of lung cancer (85-90%) are directly attributable to cigarette smoking. However, nothing is known how smoking is involved in inhibiting tumor suppressor functions of TGF-©¬ and whether or how the chemo resistance of platinum-based drugs seen in lung cancer patients who are smokers is dependent on this pathway. 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 (DMSO, as a control) to mimic the conditions of long-term cigarette smoking. Prolonged exposure of these cells to CSC resulted in decreased Smad-mediated TGF-¥â signaling due to reduced expression of Smad3 both in the protein and mRNA level. The decrease in Smad3 is due to histone deacetylation. Long-term CSC treatment reduced apoptosis, increased cell viability, decreased TGF-¥â-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. Looking further into public databases revealed that the expression of Smad3 is lower in lung tumors of current smokers compared to that observed in never-smokers. The 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-term CSC treated cells, decreased the Bcl2 levels and re-sensitized the cells to platinum-based chemotherapy. Thus, Smad3 controls the expression of Bcl2 and sensitivity 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 expression of Smad3.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-04122012-114031 |
| Date | 24 April 2012 |
| Creators | Samanta, Debangshu |
| Contributors | Pran K. Datta, Mark deCaestecker, Lawrence J. Marnett, David P. Carbone, Jin Chen |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-04122012-114031/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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