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Overexpression of Platelet-type 12-Lipoxygenase Promotes Tumor Cell Survival by Enhancing _vß₃ and _vß₅ Integrin Expression¹

Departments of Radiation Oncology [G. P. P., K. T., Y. L. C., K. V. H.], Pathology [K. V. H.], and Medicine [E. P.], Wayne State University, Detroit, Michigan 48202, and Karmanos Cancer Institute, Detroit, Michigan 48201 [K. V. H.]

Arachidonic acid metabolism leads to the generation of biologically active metabolites that regulate cell growth and proliferation, as well as survival and apoptosis. We have demonstrated previously that platelet-type 12-lipoxygenase (LOX) regulates the growth and survival of a number of cancer cells. In this study, we show that overexpression of platelet-type 12-LOX in prostate cancer PC3 cells or epithelial cancer A431 cells significantly extended their survival and delayed apoptosis when cultured under serum-free conditions. These effects were shown to be a result of enhanced surface integrin expression, resulting in a more spread morphology of the cells in culture. PC3 cells transfected with 12-LOX displayed increased _vß₃ and _vß₅ integrin expression, whereas other integrins were unaltered. Transfected A431 cells did not express _vß₃; however, _vß₅ integrin expression was increased. Treatment of both transfected cell lines with monoclonal antibody to _vß₅ (and in the case of PC3 cells, anti-_vß₃) resulted in significant apoptosis. In addition, treatment with 100 nM 12(S)-hydroxy-eicosatetraenoic acid, the end product of platelet-type 12-LOX, but not other hydroxy-eicosatetraenoic acids, enhanced the survival of wild-type PC3 and A431 cells and resulted in increased expression of _vß₅. Furthermore, Baicalein or N-benzyl-N-hydroxy-5-phenylpentamide, specific 12-LOX inhibitors, significantly decreased _vß₅-mediated adhesion and survival in 12-LOX-overexpressing cells. The results show that 12-LOX regulates cell survival and apoptosis by affecting the expression and localization of the vitronectin receptors, _vß₃ and _vß₅, in two cancer cell lines.

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