High consumption of fat, especially red meat, is a risk factor for cancer. Arachidonic acid and its precursor, linoleic acid, are major components in animal fats. Cellular metabolism of arachidonic acid by enzymes such as cyclooxygenase (COX) and lipoxygenase (LOX) generate a group of lipids, termed eicosanoids, which have potent and diverse biological activities. The eicosanoid product of 12-Lipoxygenase (12-LOX), 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], modulates tumor growth and metastasis. In the previous funding period of this grant, we characterized the expression of 12-LOX in various tumors and further elucidated its role in tumor progression. We also identified a novel protein network, comprised of beta4 integrin, lamin A, cytokeratin 5, and phosphoprotein C8FW, which interacts with 12-LOX. When paired with alpha6, beta4 integrin subunit forms a major receptor for laminin. The alpha6beta4 integrin plays a major role in hemidesmosome, an adhesion complex that anchors epithelial cells to basement membrane. Mobilization of alpha6beta4 integrin from hemidesmosomes or elevated surface expression of alpha6beta4 has been implicated in malignant progression of various carcinomas. In this proposal, we will study further our novel observation regarding interaction between 12-LOX and beta4 integrin in the context of hemidesmosome formation and dissolution, cellular signaling, and tumor cell survival, invasion, and metastasis. The following specific aims are proposed: (1) Determine the structural basis for the interaction between beta4 integrin subunit and 12-LOX; (2) Study how alpha6beta4 regulates 12-LOX cellular localization and activity; (3) Determine whether 12-LOX regulates the function of alpha6beta4 in hemidesmosomes; (4) Study whether and how 12-LOX and beta4 integrin contribute to the survival of carcinoma cells; and (5) Determine whether and how 12-LOX and beta4 collaborate in carcinoma invasion in vitro and tumor progression in animal models. The proposed studies, when accomplished, will provide significant insights into eicosanoid regulation of tumor progression.
Showing the most recent 10 out of 102 publications
