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Focal adhesion kinase regulation of Cox-2 in lung cancer

Institution: Scripps Research Institute
Investigator(s): Satyajit Mitra, Ph.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12FT-0122 Award: $74,520
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Oxidants contained in tobacco smoke induce acute inflammatory response in epithelial cells that line the airway and lung. Cycloxygenase-2 (Cox-2) protein levels are induced in response to these inflammatory responses to smoking, and Cox-2 levels increase during the processes of cell transformation into cancer. Studies conducted with heavy cigarette smokers showed that pharmacological drugs designed to block Cox-2 function reduced the incidence of lung cancers. However, the normal regulation of Cox-2 expression in normal and lung cancer cells is largely unknown.

Our interest is in the relationship between cell adhesion events and Cox-2 expression. A signaling kinase, called Focal Adhesion Kinase (FAK) that integrates inputs from growth factors and adhesion molecules, becomes increased in activity in several forms of human cancer. Therefore, we hypothesize that FAK signaling connections to Cox-2 reflect a physiological pathway in normal lung cells that may contribute to malignancy of lung cancer.

We propose to study how FAK controls Cox-2 expression levels in lung adenocarcinoma cells, and we will test whether a combination strategy of anti-FAK and anti-Cox-2 treatments are more effective than blockade of Cox-2 alone in inhibiting the growth of lung cancer cells as tumors. These studies will be performed in genetically modified cells with both removal and reconstituted FAK. This will enable us to develop information on the association of FAK signaling events with Cox-2 gene regulation, and dissect the signaling pathways that are involved. As the project evolves, we will carry out cellular and signaling analyses of lung carcinoma cells in culture, and hope to confirm our results in animal models of lung cancer.

The completion of these studies will form the foundation for drug targeting of FAK used alone or in combination with other drugs in the therapy of human lung cancer.
Publications

Control of motile and invasive cell phenotypes by focal adhesion kinase.
Periodical: Biochim. Biophy. Index Medicus:
Authors: Schlaepfer DD, Mitra SK, Ilic D ART
Yr: 2004 Vol: 1692 Nbr: Abs: Pg: 77-102

Multiple connections link FAK to cell motility and invasion.
Periodical: Current Opinion Genetic Development Index Medicus:
Authors: Schlaepfer DD, Mitra SK ART
Yr: 2004 Vol: 14 Nbr: Abs: Pg: 92-101