Document Detail


Long-term smoking mediated down-regulation of Smad3 induces resistance to carboplatin in non-small cell lung cancer.
MedLine Citation:
PMID:  22904681     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
While numerous cell signaling pathways are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the Smad-dependent transforming growth factor β pathway on the therapeutic outcome. Previous reports suggested that patients with lung cancer who continue to smoke while receiving chemotherapy have a poorer outcome than their nonsmoking counterparts do. In our previous study, we showed that long-term cigarette smoke condensate (CSC)-mediated down-regulation of Smad3 induces tumorigenesis. The objective of this study was to determine the mechanism of function of Smad3 in chemoresistance induced by CSC in human lung cell lines, namely, A549 and HPL1A. Long-term CSC treatment increases the half-maximal inhibitory concentration (IC(50)) of carboplatin and makes cells resistant to carboplatin. The increase in IC(50) of long-term CSC-treated cells is due to the reduced induction in apoptosis by carboplatin. The increase in IC(50) and decrease in apoptosis in long-term CSC-treated cells is correlated with the expression of Bcl2. We have determined that Bcl2 is both necessary and sufficient to make the cells resistant to carboplatin. We have also shown that Smad3 acts upstream to regulate the expression of Bcl2 specifically and, thus, sensitivity of the cells to carboplatin. This is supported by the inverse correlation between the expressions of Smad3 and Bcl2 in human lung tumors. Collectively, these data suggest that loss of Smad3 expression in CSC-treated cells induces resistance to carboplatin by upregulating the expression of Bcl2. This study explains, at least in part, the higher chemoresistance rate observed in smokers.
Authors:
Debangshu Samanta; Jacob Kaufman; David P Carbone; Pran K Datta
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  14     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2013-03-18     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  644-55     Citation Subset:  IM    
Affiliation:
Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Apoptosis / drug effects,  genetics
Biphenyl Compounds / pharmacology
Carboplatin / pharmacology*
Carcinoma, Non-Small-Cell Lung / genetics*
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Neoplastic* / drug effects
Humans
Lung Neoplasms / genetics*
Nitrophenols / pharmacology
Piperazines / pharmacology
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors,  genetics,  metabolism
Smad3 Protein / genetics*,  metabolism
Smoking / adverse effects*
Sulfonamides / pharmacology
Grant Support
ID/Acronym/Agency:
5P50CA90949/CA/NCI NIH HHS; CA113519/CA/NCI NIH HHS; P30DK058404/DK/NIDDK NIH HHS; R01 CA95195/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/ABT-737; 0/Antineoplastic Agents; 0/Biphenyl Compounds; 0/Nitrophenols; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Smad3 Protein; 0/Sulfonamides; 41575-94-4/Carboplatin
Comments/Corrections

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