Mutations in oncogenes and tumor suppressor genes in animal and human tumors may give important clues as to the exposures that led to the tumors. For rodent neoplasms that are pathologically similar to the corresponding human cancer, the rodent disease may be used to model the cellular events involved and to study prevention and therapy. Currently, we are focusing on the K-ras gene in lung cancer. In studies of the role of the oncogene K-ras in genesis of adenocarcinoma of the lung, we are utilizing a mouse model, including tumors induced in vivo, and normal immortalized and transformed alveolar type 2 cells in vitro. An important question is why mutant K-ras is actively oncogenic, since wild-type K-ras is a tumor suppressor. An answer to this question could aid in prevention of up to 50% of human lung adenocarcinomas, and an even higher percentage of cancers of the colon and pancreas. We have been pursuing the hypothesis that high activity of mutant K-ras leads to generation of reactive oxygen species, which damage DNA and so lead to malignant transformation. We have expressed mutant K-ras in nontransformed lung epithelial cells, and demonstrated increase in several forms of reactive oxygen, including peroxides and superoxide, and DNA damage. Sources of the reactive oxygen include the lung cancer-associated enzyme COX2, and NADPH oxidase. Induction of these toxic effects is followed shortly by upregulation of anti-oxidant enzymes, including superoxide dismutase and peroxidoredoxins, then damping out of the damage. Thus anti-oxidant defenses is an important aspect of the carcinogenic process here. These parameters are also being studied in human lung adenocarcinonma cell lines, and primary human lung cancers are being collected via the Human Cooperative Tissue Network. Results will have applicability for prevention and possibly therapy of human lung cancer.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005399-20
Application #
6949858
Study Section
(LCC)
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2003
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Sithanandam, Gunamani; Fornwald, Laura W; Fields, Janet R et al. (2012) Anti-tumor efficacy of naked siRNAs for ERBB3 or AKT2 against lung adenocarcinoma cell xenografts. Int J Cancer 130:251-8
Sithanandam, G; Anderson, L M (2008) The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther 15:413-48
Romanowska, Malgorzata; Kikawa, Keith D; Fields, Janet R et al. (2007) Effects of selenium supplementation on expression of glutathione peroxidase isoforms in cultured human lung adenocarcinoma cell lines. Lung Cancer 55:35-42
Sithanandam, Gunamani; Smith, George T; Fields, Janet R et al. (2005) Alternate paths from epidermal growth factor receptor to Akt in malignant versus nontransformed lung epithelial cells: ErbB3 versus Gab1. Am J Respir Cell Mol Biol 33:490-9
Sithanandam, Gunamani; Fornwald, Laura W; Fields, Janet et al. (2005) Inactivation of ErbB3 by siRNA promotes apoptosis and attenuates growth and invasiveness of human lung adenocarcinoma cell line A549. Oncogene 24:1847-59
Anderson, Lucy M (2005) Cancer biology and hormesis: comments on Calabrese (2005). Crit Rev Toxicol 35:583-6
Maciag, Anna; Anderson, Lucy M (2005) Reactive oxygen species and lung tumorigenesis by mutant K-ras: a working hypothesis. Exp Lung Res 31:83-104
Vucenik, Ivana; Ramakrishna, Gayatri; Tantivejkul, Kwanchanit et al. (2005) Inositol hexaphosphate (IP6) blocks proliferation of human breast cancer cells through a PKCdelta-dependent increase in p27Kip1 and decrease in retinoblastoma protein (pRb) phosphorylation. Breast Cancer Res Treat 91:35-45
Dennis, Phillip A; Van Waes, Carter; Gutkind, J Silvio et al. (2005) The biology of tobacco and nicotine: bench to bedside. Cancer Epidemiol Biomarkers Prev 14:764-7
Maciag, Anna; Sithanandam, Gunamani; Anderson, Lucy M (2004) Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Carcinogenesis 25:2231-7

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