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PMID: 16601104 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 16 ·2006-04-18 ·Pages 6332-7

Dasgupta P, Kinkade R, Joshi B, Decook C, Haura E, Chellappan S

Abstract

Non-small cell lung cancer (NSCLC) demonstrates a strong etiologic association with smoking. Although nicotine is not carcinogenic, it can induce cell proliferation and angiogenesis and suppress apoptosis induced by certain agents. Here we show that nicotine inhibits apoptosis induced by the drugs gemcitabine, cisplatin, and taxol, which are used to treat NSCLCs. This protection correlated with the induction of XIAP and survivin by nicotine in a panel of human NSCLC cell lines, and depletion of XIAP and survivin ablated the protective effects of nicotine. The antiapoptotic effects of nicotine were mediated by dihydro beta-erythroidine-sensitive alpha3-containing nicotinic acetylcholine receptors and required the Akt pathway. Chromatin immunoprecipitation assays demonstrated that nicotine stimulation caused an increased recruitment of E2F1 and concomitant dissociation of retinoblastoma tumor suppressor protein (Rb) from survivin promoter in A549 cells. Moreover, ablation of E2F1 levels caused abrogation of the protective effects of nicotine against cisplatin-induced apoptosis in A549 cells whereas ablation of signal transducer and activator of transcription 3 levels had no effect. These studies suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that survivin and XIAP play a key role in the antiapoptotic activity of nicotine.

MeSH Terms
Antineoplastic Agents/antagonists & inhibitors,therapeutic use Apoptosis/drug effects Carcinoma, Non-Small-Cell Lung/drug therapy,metabolism Cell Line, Tumor Chromatin Immunoprecipitation Cisplatin/antagonists & inhibitors,therapeutic use Deoxycytidine/analogs & derivatives,antagonists & inhibitors,therapeutic use Dihydro-beta-Erythroidine/pharmacology Drug Resistance, Neoplasm/drug effects Humans Inhibitor of Apoptosis Proteins Lung Neoplasms/drug therapy,metabolism Microtubule-Associated Proteins/genetics,metabolism Neoplasm Proteins/genetics,metabolism Nicotine/pharmacology Paclitaxel/antagonists & inhibitors,therapeutic use Promoter Regions, Genetic Receptors, Nicotinic/drug effects,metabolism Retinoblastoma Protein/metabolism Survivin Up-Regulation X-Linked Inhibitor of Apoptosis Protein/genetics,metabolism
Chemicals
Antineoplastic Agents BIRC5 protein, human Inhibitor of Apoptosis Proteins Microtubule-Associated Proteins Neoplasm Proteins Receptors, Nicotinic Retinoblastoma Protein Survivin X-Linked Inhibitor of Apoptosis Protein XIAP protein, human Deoxycytidine Dihydro-beta-Erythroidine Nicotine gemcitabine Paclitaxel Cisplatin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Dasgupta Piyali
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33647, USA.
Kinkade Rebecca
Joshi Bharat
Decook Christina
Haura Eric
Chellappan Srikumar
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0509313103
Published
2006-04-18
Epub
2006-00-06
Pages
6332-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1458878
Subset
IM
Grants
NCI NIH HHS · R01 CA063136 · United States
NCI NIH HHS · CA63136 · United States
External Links
PubMed source DOI: 10.1073/pnas.0509313103 PMC Full Text View journal details
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