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Carcinogenesis Advance Access published online on February 28, 2008
Carcinogenesis, doi:10.1093/carcin/bgn041
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma

Hildegard M. Schuller1, Hussein A. N. Al-Wadei1,2 and Mourad Majidi1

Experimental Oncology Laboratory
1 Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA and Sana'a University
2 Sana'a, Yemen

Author for correspondence and reprint requests: Dr. H. M. Schuller, Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, Phone: 865-974-8217, Fax: 865-974-5616, e-mail: hmsch{at}utk.edu

Pulmonary adenocarcinoma (PAC) is the leading type of lung cancer in smokers and non-smokers that arises in most cases from small airway epithelial cells. PAC has a high mortality due to its aggressive behavior and resistance to cancer therapeutics. We have previously shown that the proliferation of human PAC cells NCI-H322 and immortalized human small airway epithelial cells HPL1D is stimulated by cAMP/PKA dependent phosphorylation of CREB and transactivation of the EGFR and that this pathway is activated by β1-adrenoreceptors (β1-ARs) and the non genomic estrogen receptor beta (ERβ). Our current in vitro studies with HPL1D and NCI-H322 cells showed that signaling via the GABAB receptor (GABABR) strongly inhibited base level and isoproterenol-induced cAM, p-CREB, CRE-luciferase activity and p-ERK1/2 and effectively blocked DNA synthesis and cell migration. The inhibitory effects of GABA were disinhibited by the GABAB receptor antagonist CGP35348 or GABABR knockdown. Immunohistochemical investigation of hamster lungs showed significant underexpression of GABA in animals with small airway-derived PACS induced by the nicotine-derived carcinogen NNK. These findings suggest that GABA may have tumor suppressor function in small airway epithelia and the PACs derived from them and that downregulation of GABA by NNK may contribute to the development of this cancer in smokers. Our findings suggest that marker-guided treatment with GABA or a GABABR agonist of individuals with downregulated pulmonary GABA may provide a novel targeted approach for the prevention of PAC in smokers

Received January 8, 2008; revised January 29, 2008; accepted January 29, 2008.


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