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Carcinogenesis Advance Access originally published online on February 28, 2008
Carcinogenesis 2008 29(10):1979-1985; 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
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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

1 Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA
2 Department of Preventive Medicine, Sana'a University, Sana'a, Yemen

* To whom correspondence should be addressed. Tel: +1 865 974 8217; Fax: +1 865 974 5616; Email: 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 shown previously that the proliferation of human PAC cells NCI-H322 and immortalized human small airway epithelial cells HPL1D is stimulated by cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein and transactivation of the epidermal growth factor receptor and that this pathway is activated by beta-1-adrenoreceptors (β1-ARs) and the non-genomic estrogen receptor beta. Our current in vitro studies with HPL1D and NCI-H322 cells showed that signaling via the gamma-amino butyric acid receptor (GABABR) strongly inhibited base level and isoproterenol-induced cAMP, p-CREB, cyclic adenosine monophosphate response element-luciferase activity and p-extracellular regulated kinase-1 (ERK1)/2 and effectively blocked DNA synthesis and cell migration. The inhibitory effects of gamma-amino butyric acid (GABA) were disinhibited by the GABABR antagonist CGP-35348 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 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (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.

Abbreviations: ANOVA, analysis of variance; β-AR, beta-adrenoreceptor; BrdU, Bromodeoxyuridine; cAMP, cyclic adenosine monophosphate; CRE, cyclic adenosine monophosphate response element; CREB, cyclic adenosine monophosphate response element binding; EGFR, epidermal growth factor receptor; ERK1, extracellular regulated kinase-1; GABA, gamma-amino butyric acid; GABABR, gamma-amino butyric acid receptor; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PAC, pulmonary adenocarcinoma; PBS, phosphate buffered saline; PDAC, pancreatic ductal adenocarcinoma; PKA, protein kinase A

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


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