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Tobacco oxidants, EGF receptor stability, and lung disease

Institution: University of California, Davis
Investigator(s): Elaine Khan, Ph.D.
Award Cycle: 2004 (Cycle 13) Grant #: 13FT-0126 Award: $75,000
Subject Area: Pulmonary Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
According to the American Lung Association, “Lung cancer has become the leading cause of cancer mortality in both men and women in the United States and will cause an estimated 157,200 deaths in 2003, accounting for 28% of all cancer deaths.” It is estimated that 87% of lung cancer cases are caused by smoking. Smokers have about a 20-fold increase in lung cancer risk compared to non-smokers and the risk increases with the duration of smoking and amount smoked per day. Cigarette smoke contains abundant free radical species and reactive oxidants, which have been suggested to play a role in cigarette smoke-induced adverse health effects. Although the connection between smoking and lung cancer is clear, the mechanism by which smoking leads to lung cancer is poorly understood. One proposed mechanism suggests that absorption of tobacco smoke reactive oxidants, such as hydrogen peroxide (H2O2), by lung epithelial cells may have dire consequences on cell function.

ErbB1, the epidermal growth factor receptor (EGFR), is involved in regulation of growth of many cell types, particularly epithelial cells. The ability of the activated EGFR to terminate its signaling via a process of degradation is crucial for normal cell function. In situations where cells are unable to degrade EGFR and terminate its function, extensive cell growth and cancer development can occur. Our hypothesis is that reactive oxidants, such as H2O2, in cigarette smoke cause alterations of the EGFR that result in prolonged signaling due to its inability to be degraded. The goal of the proposed project is to determine how exposure of lung epithelial cells to environmental tobacco smoke (ETS) or H2O2 may prolong signaling by the EGFR. We will characterize the effects of ETS or H2O2 exposure on EGFR activation and its signaling termination. We will also examine alterations in the signaling components which are activated by EGFR that may lead to uncontrolled growth in the lung epithelium.

Characterization of the pathways involved in lung injury or hyperplasia at the molecular and cellular level is crucial not only for the understanding of how cigarette smoking leads to lung cancer, but also for identifying specific targets for the development of therapeutic and pharmacological strategies to block the deleterious effects of tobacco smoke reactive oxidants. These therapies would benefit those who continue to smoke despite knowledge of the health risks as well those affected by their secondhand smoke.