FOXO3a elicits a pro-apoptotic transcription program and cellular response to human lung carcinogen nicotine-derived nitrosaminoketone (NNK).

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.