title: FOXO3a elicits a pro-apoptotic transcription program and cellular response to human lung carcinogen nicotine-derived nitrosaminoketone (NNK).
abstract: Long-term carcinogen exposure exerts continuous pressure on key mechanisms that repair or eliminate carcinogen-damaged cells giving rise to selective failures that contribute to lung cancer. FOXO3a is a transcription factor that elicits a protective response to diverse cellular stresses. Although implicated as a tumor suppressor, its role in sporadic cancer is uncertain. We recently observed that FOXO3a gene inactivation occurs frequently in carcinogen-induced lung adenocarcinoma (LAC). This suggests that FOXO3a may play a role in LAC suppression by eliciting a protective response to carcinogenic stress. Here we investigated this possibility by examining the role of FOXO3a in the cellular response to nicotine-derived nitrosaminoketone (NNK), a lung carcinogen implicated as a cause of human LAC. We show that restoration of FOXO3a in FOXO3a-deficient LAC cells increases sensitivity to apoptosis caused by a DNA-damaging intermediate of NNK. Prior to this cellular outcome, FOXO3a is functionally activated and mediates a large-scale transcription program in response to this damage involving a significant modulation of 440 genes. Genes most significantly represented in this program are those with roles in cell growth and proliferation>protein synthesis>gene expression>cell death>cell cycle. The results of this study show that FOXO3a directs an anti-carcinogenic transcription program that culminates in the elimination of carcinogen-damaged cells. This suggests that FOXO3a is a potential suppressor of carcinogenic damage in LAC.
authors.affiliation: Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Blake
authors.forename: Oliver R
authors.initials: OR
authors.lastname: Mikse
authors.forename: Willard M
authors.initials: WM
authors.lastname: Freeman
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Herzog
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced* / Q000235:genetics; D017209:Apoptosis / Q000235:genetics*; D002273:Carcinogens / Q000633:toxicity*; D045744:Cell Line, Tumor; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics; D009538:Nicotine / Q000737:chemistry / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002273:Carcinogens; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009602:Nitrosamines; D025521:Tumor Suppressor Proteins; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone