Lung cancer is the leading cause of cancer death in the United States. Pulmonary adenocarcinoma (PAC) accounts for about 60 percent of all lung cancer cases with a mortality of >95 percent within one year of diagnosis. The long-term goal of this project is to identify novel molecular targets involved in the growth regulation of PAC and their normal cells of origin (small airway epithelia, SAE), the genetic make-up of which may determine susceptibility to smoking-associated PAC, and to identify the nature of changes to components of this pathway(s) caused by the nicotine-derived carcinogenic nitrosamine NNK. Our data provide evidence that the growth of human PAC cell lines and SAE is under beta-adrenergic control via the beta-adrenergic receptor-mediated release of arachidonic acid (AA). Furthermore, we have shown that NNK is a high affinity agonist for beta1 and beta2-adrenergic receptors and stimulates this AA-dependent mitogenic pathway. Based on these findings, we propose the following specific aims. 1. To determine if beta1 or beta2 or both of these adrenergic receptors mediate the observed AA-dependent stimulation of DNA synthesis, and to characterize the downstream effectors of these pathways. 2. To determine which products of the AA cascade are formed in untreated cells and in response to NNK, which of these products stimulate DNA synthesis, and what downstream effectors are activated by these products.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088809-04
Application #
6874971
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Poland, Alan P
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$289,962
Indirect Cost
Name
University of Tennessee Knoxville
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
003387891
City
Knoxville
State
TN
Country
United States
Zip Code
37996
Schuller, Hildegard M (2013) Effects of tobacco constituents and psychological stress on the beta-adrenergic regulation of non-small cell lung cancer and pancreatic cancer: implications for intervention. Cancer Biomark 13:133-44
Cekanova, Maria; Majidy, Mourad; Masi, Thomas et al. (2007) Overexpressed Raf-1 and phosphorylated cyclic adenosine 3'-5'-monophosphatate response element-binding protein are early markers for lung adenocarcinoma. Cancer 109:1164-73
Majidi, Mourad; Al-Wadei, Hussein A; Takahashi, Takashi et al. (2007) Nongenomic beta estrogen receptors enhance beta1 adrenergic signaling induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human small airway epithelial cells. Cancer Res 67:6863-71
Al-Wadei, Hussein A N; Takahashi, Takashi; Schuller, Hildegard M (2006) Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by beta-carotene via activation of cAMP, PKA, CREB and ERK1/2. Int J Cancer 118:1370-80
Schuller, Hildegard M; Kabalka, George; Smith, Gary et al. (2006) Detection of overexpressed COX-2 in precancerous lesions of hamster pancreas and lungs by molecular imaging: implications for early diagnosis and prevention. ChemMedChem 1:603-10
E, Laag; M, Majidi; M, Cekanova et al. (2006) NNK activates ERK1/2 and CREB/ATF-1 via beta-1-AR and EGFR signaling in human lung adenocarcinoma and small airway epithelial cells. Int J Cancer 119:1547-52
Cekanova, Maria; Masi, Thomas; Plummer 3rd, Howard K et al. (2006) Pulmonary fibroblasts stimulate the proliferation of cell lines from human lung adenocarcinomas. Anticancer Drugs 17:771-81
Al-Wadei, Hussein A N; Schuller, Hildegard M (2006) Cyclic adenosine monophosphate-dependent cell type-specific modulation of mitogenic signaling by retinoids in normal and neoplastic lung cells. Cancer Detect Prev 30:403-11
Al-Wadei, H A N; Takahasi, T; Schuller, H M (2005) PKA-dependent growth stimulation of cells derived from human pulmonary adenocarcinoma and small airway epithelium by dexamethasone. Eur J Cancer 41:2745-53
Masi, Thomas; Cekanova, Maria; Walker, Kindra et al. (2005) Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary adenocarcinomas in Syrian golden hamsters contain beta 2-adrenergic receptor single-nucleotide polymorphisms. Genes Chromosomes Cancer 44:212-7

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