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Tobacco carcinogen NNK transporter MRP2 regulates CFTR function in lung epithelia: implications for lung cancer

Chunying Li1, John D Schuetz, Anjaparavanda P Naren

  • 1Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 540 E. Canfield Avenue, 5312 Scott Hall, Detroit, MI 48201, USA.

Cancer Letters
|January 22, 2010
PubMed

Insights

Lung epithelial cells defend against carcinogens using apical transporters like multidrug resistance protein-2 (MRP2) and cystic fibrosis transmembrane conductance regulator (CFTR). These proteins form a complex, aiding lung defense against tobacco smoke exposure.

Area of Science:

  • Cell Biology
  • Pulmonary Medicine
  • Toxicology

Background:

  • Lung cancer is a leading cause of cancer death, with tobacco smoke being a primary risk factor.
  • Tobacco smoke contains numerous carcinogens, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
  • The lung epithelium's apical surface plays a crucial role in defending against inhaled toxins.

Purpose of the Study:

  • To investigate the role of apical ATP-binding cassette (ABC) transporters in lung epithelial defense against tobacco carcinogens.
  • To determine the localization and functional interaction of multidrug resistance protein-2 (MRP2) and cystic fibrosis transmembrane conductance regulator (CFTR) in lung epithelial cells.

Main Methods:

  • Utilized polarized lung epithelial cell models.
  • Investigated the apical localization of MRP2 and CFTR using immunofluorescence.
  • Examined the functional coupling and macromolecular complex formation between MRP2, CFTR, and PDZ proteins.

Main Results:

  • Multidrug resistance protein-2 (MRP2) and cystic fibrosis transmembrane conductance regulator (CFTR) were confirmed to be localized at the apical surface of polarized lung epithelial cells.
  • A functional coupling between CFTR and MRP2 was observed, potentially mediated by PDZ proteins.
  • Evidence of a macromolecular complex involving CFTR, MRP2, and PDZ proteins was found, suggesting regulatory cooperation.

Conclusions:

  • CFTR and MRP2 form a functional complex at the apical surface of lung epithelial cells, contributing to native defense mechanisms.
  • This complex may play a significant role in the lung's response to tobacco smoke and its associated diseases.
  • Findings have implications for understanding and potentially treating smoke-related lung diseases like COPD and lung cancer.

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