Tobacco carcinogen NNK transporter MRP2 regulates CFTR function in lung epithelia: implications for lung cancer.
Lung cancer is the leading cause of cancer death in the United States. About 85% of all lung cancers are linked to tobacco smoke, in which more than 50 lung carcinogens have been identified and one of the most abundant is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The human lung epithelium constitutes the first line of defense against tobacco-specific carcinogens, in which apically-localized receptors, transporters, and ion channels in the airway may play a critical role in this native defense against tobacco smoke. Here we showed that multidrug resistance protein-2 (MRP2) and cystic fibrosis transmembrane conductance regulator (CFTR), two ATP-binding cassette (ABC) transporters, are localized to the apical surfaces of plasma membrane in polarized lung epithelial cells. We observed that there is a functional coupling between CFTR and MRP2 that may be mediated by PDZ proteins. We also observed the existence of a macromolecular complex containing CFTR, MRP2, and PDZ proteins, which might form the basis for the regulatory cooperation between these two ABC transporters. Our results have important implications for cigarette smoke-associated lung diseases (such as smoke-related emphysema, chronic obstructive pulmonary disease, and lung cancer).
Li
Chunying
C
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 540 E. Canfield Avenue, 5312 Scott Hall, Detroit, MI 48201, USA.
Schuetz
John D
JD
Naren
Anjaparavanda P
AP
D000818:Animals; D002273:Carcinogens / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008856:Microscopy, Fluorescence; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D009602:Nitrosamines / Q000378:metabolism* / Q000494:pharmacology
D002273:Carcinogens; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009602:Nitrosamines; C000715087:ABCC2 protein, human; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone