Induction of plasminogen activator by 12-O-tetradecanoylphorbol-13-acetate and calcium ionophore. Suppression by inhibitors of fatty acid lipoxygenase.
HeLa cells incubated with 12-O-tetradecanoylphorbol-13-acetate (TPA), and rat basophilic leukemia (RBL-1) cells incubated with calcium ionophore, showed increased levels of the protease plasminogen activator. These treatments have previously been shown to stimulate the cellular metabolism of arachidonic acid. The induction of plasminogen activator in both cell types was inhibited in a dose-dependent manner by 5,8,11,14-eicosatetraynoic acid and nordihydroguaiaretic acid, two compounds known to inhibit arachidonate metabolism via lipoxygenases. In contrast, indomethacin, which selectively inhibits arachidonate metabolism via cyclooxygenase, was inactive. The levels of four enzyme markers in HeLa cells were unchanged by treatment with TPA plus the lipoxygenase inhibitors, indicating that the inhibitors did not exert their effects on plasminogen activator via general cell toxicity. HeLa cells preincubated with [3H]arachidonate and subsequently challenged with TPA produced small amounts of material with the chromatographic mobilities and resistance to indomethacin expected of hydroxylated fatty acids derived via lipoxygenase. RBL-1 cells have been shown previously to produce leukotrienes and other lipoxygenase metabolites when treated with calcium ionophore. Plasminogen activator in HeLa cells was stimulated by up to 2.5-fold by incubation with 0.5-2 micrograms/ml 5-hydroxyeicosatetraenoic acid. Our results suggest that the induction of plasminogen activator in HeLa and RBL-1 cells is not mediated by prostaglandins or thromboxanes, but may be mediated or modulated by arachidonate metabolites derived via a lipoxygenase pathway.
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D005227:Fatty Acids; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids; D007942:Leukemia, Experimental / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol; D010704:Phorbols / Q000494:pharmacology*; D010960:Plasminogen Activators / Q000096:biosynthesis*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001095:Arachidonic Acids; D002396:Catechols; D005227:Fatty Acids; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D010704:Phorbols; D015117:5,8,11,14-Eicosatetraynoic Acid; D016718:Arachidonic Acid; D000001:Calcimycin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D009637:Masoprocol; D010960:Plasminogen Activators; D013755:Tetradecanoylphorbol Acetate