Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin.
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.
Dasgupta
Piyali
P
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
R
Joshi
Bharat
B
Decook
Christina
C
Haura
Eric
E
Chellappan
Srikumar
S
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D000077022:Survivin; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011978:Receptors, Nicotinic; D016160:Retinoblastoma Protein; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003841:Deoxycytidine; D004079:Dihydro-beta-Erythroidine; D009538:Nicotine; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine