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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / antagonists & inhibitors*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects*
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / metabolism*
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Cell Line, Tumor
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Chromatin Immunoprecipitation
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Cisplatin / antagonists & inhibitors
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Cisplatin / therapeutic use
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / antagonists & inhibitors
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Deoxycytidine / therapeutic use
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Dihydro-beta-Erythroidine / pharmacology
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Drug Resistance, Neoplasm / drug effects*
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Gemcitabine
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Humans
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Inhibitor of Apoptosis Proteins
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism*
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nicotine / pharmacology*
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Paclitaxel / antagonists & inhibitors
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Paclitaxel / therapeutic use
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Promoter Regions, Genetic
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Receptors, Nicotinic / drug effects
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Receptors, Nicotinic / metabolism
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Retinoblastoma Protein / metabolism
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Survivin
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Up-Regulation
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism*
Substances
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Antineoplastic Agents
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BIRC5 protein, human
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Receptors, Nicotinic
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Retinoblastoma Protein
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Survivin
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Deoxycytidine
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Dihydro-beta-Erythroidine
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Nicotine
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Paclitaxel
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Cisplatin
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Gemcitabine