Regulation of 12(S)-Hete Production in Tumor Cells

Abstract

12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] is a major 12-lipoxygenase (12-LOX) metabolite of arachidonic acid (AA) (Chen et al., 1992a). Previously, we have shown that exogenous 12(S)-HETE increases tumor cell adhesion to endothelium (Grossi et al., 1989; Honn et al., 1992), induces large vessel and microvessel endothelial cell retraction (Honn et al., 1989; Tang et al., 1992) and stimulates tumor cell spreading on matrix (Timar et al., 1992). Tumor cells express a variety of adhesion molecules. Among them, integrin αIIbβ3 is an important receptor for tumor cell-host cell and tumor cell-matrix interaction (Chen et al., 1992b; Chang et al., 1992a). Pretreatment of tumor cells with exogenous 12(S)-HETE enhances their adhesion to and spreading on fibronectin, which is mediated exclusively by αIIbβ3 receptors and in a cytoskeleton-dependent manner (Chopra et al., 1991; Timar et al., 1992). Besides the effects on integrins, 12(S)-HETE also appears to regulate other factors which are important to tumor cell metastasis. Pretreatment of tumor cells with 12(S)-HETE stimulates their motility (Timar et al., 1993) and release of cathepsin B (Honn et al., 1994) a proteinase associated with tumor cell invasiveness. Interestingly, we observed that treatment of W256 cells with 12(S)-HETE induced an increase in membrane-associated PKC activity (Liu et al., 1991). This activation of PKC by 12(S)-HETE also was observed in B16a cells (Liu et al., unpublished). Since only the PKCα isozyme was found in B16a cells by western blotting, it suggests that 12(S)-HETE can up-regulate PKCα activity in these cells.