Document Detail


Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreatic adenocarcinoma.
MedLine Citation:
PMID:  23308043     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Smoking is a significant risk factor for pancreatic cancer, but the molecular mechanisms by which tobacco smoke components promote the growth and progression of these cancers are not fully understood. While nicotine, the addictive component of tobacco smoke, is not a carcinogen, it has been shown to promote the growth of non-small cell lung and pancreatic cancers in a receptor-dependent fashion. Here, we show that stimulation of pancreatic cancer cells with nicotine concentrations that are within the range of human exposure results in activation of Src kinase, which facilitated the induction of the inhibitor of differentiation-1 (Id1) transcription factor. Depletion of Id1 prevented nicotine-mediated induction of proliferation and invasion of pancreatic cancer cells, indicating that it is a major mediator of nicotine function. Nicotine could promote the growth and metastasis of pancreatic cancers orthotopically implanted into SCID mice; in addition, cells stably expressing a short hairpin RNA for Id1 did not grow or metastasize in response to nicotine. Nicotine could also confer resistance to apoptosis induced by gemcitabine in pancreatic cancer cells in vitro and depletion of Src or Id1 rendered the cells sensitive to gemcitabine. Further, nicotine could effectively inhibit the chemotherapeutic effects of gemcitabine on pancreatic tumors xenografted into mice. Clinical analyses of resected pancreatic cancer specimens demonstrated a statistically significant correlation between Id1 expression and phospho-Src, tumor grade/differentiation, and worsening overall patient survival. These results demonstrate that exposure to tobacco smoke components might promote pancreatic cancer progression, metastasis, and chemoresistance and highlight the role of Id1 in these processes.
Authors:
José G Treviño; Smitha Pillai; Sateesh Kunigal; Sandeep Singh; William J Fulp; Barbara A Centeno; Srikumar P Chellappan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  14     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2013-01-11     Completed Date:  2013-07-10     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  1102-14     Citation Subset:  IM    
Affiliation:
Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / drug therapy,  metabolism*,  secondary
Animals
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cell Survival / drug effects
Deoxycytidine / analogs & derivatives,  pharmacology,  therapeutic use
Drug Resistance, Neoplasm / drug effects
Humans
Inhibitor of Differentiation Protein 1 / genetics,  metabolism*
Kaplan-Meier Estimate
Mice
Mice, SCID
Nicotine / metabolism*,  pharmacology
Pancreatic Neoplasms / drug therapy,  metabolism*,  pathology
RNA, Small Interfering
Signal Transduction / drug effects
Transcription, Genetic / drug effects
src-Family Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
CA139612/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Inhibitor of Differentiation Protein 1; 0/RNA, Small Interfering; 54-11-5/Nicotine; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC 2.7.10.2/src-Family Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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