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FOXO3a elicits a pro-apoptotic transcription program and cellular response to human lung carcinogen nicotine-derived

Daniel C Blake1, Oliver R Mikse, Willard M Freeman

  • 1Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA.

Lung Cancer (Amsterdam, Netherlands)
|April 22, 2009
PubMed

Insights

FOXO3a acts as a tumor suppressor by initiating a protective response against lung carcinogens. Restoring FOXO3a in lung adenocarcinoma cells enhances apoptosis, eliminating damaged cells and preventing cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Carcinogen exposure causes cellular damage, leading to lung cancer.
  • FOXO3a is a transcription factor involved in cellular stress response and tumor suppression, but its role in sporadic cancers is unclear.
  • FOXO3a gene inactivation is common in carcinogen-induced lung adenocarcinoma (LAC).

Purpose of the Study:

  • To investigate the role of FOXO3a in the cellular response to the lung carcinogen nicotine-derived nitrosaminoketone (NNK).
  • To determine if FOXO3a acts as a tumor suppressor in lung adenocarcinoma by protecting against carcinogenic stress.

Main Methods:

  • Examined the effect of FOXO3a restoration in FOXO3a-deficient LAC cells exposed to NNK.
  • Analyzed the transcriptional program mediated by FOXO3a in response to NNK-induced DNA damage.
  • Assessed cellular sensitivity to apoptosis.

Main Results:

  • Restoration of FOXO3a in LAC cells increased apoptosis induced by NNK's DNA-damaging intermediate.
  • FOXO3a activation mediated a large-scale transcription program involving 440 genes.
  • Key genes modulated by FOXO3a are involved in cell growth, proliferation, protein synthesis, gene expression, cell death, and the cell cycle.

Conclusions:

  • FOXO3a directs an anti-carcinogenic transcription program that eliminates carcinogen-damaged cells.
  • FOXO3a functions as a suppressor of carcinogenic damage in lung adenocarcinoma.
  • FOXO3a represents a potential therapeutic target for lung cancer prevention and treatment.

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