The ability of various inhibitors of lipoxygenase (LOX) enzymes and 5-lipoxygenase-activating protein (FLAP) to induce apoptosis has implicated these pathways in the mechanism(s) of this form of cell death. Although FLAP plays an important role in 5-LOX activity, this protein is found at high levels in some cells lacking LOX, suggesting it might mediate other effects. Furthermore, the concentration of MK886, a FLAP inhibitor, required to induce apoptosis is ≈ 100-fold more than that required to inhibit LOX, and this compound remains effective in cells lacking LOX. The present study examines the role of FLAP in MK886-induced apoptosis. MK886 induced apoptosis in WSU cells, a human chronic lymphocytic leukaemia cell line that lacks FLAP protein and mRNA, suggesting that this agent is acting independently of FLAP. This conclusion was further supported by the fact that a more specific FLAP inhibitor, MK591, induced only minimal apoptosis in FL5.12 cells, a murine prolymphoid cell line containing FLAP. The role of FLAP was examined more directly by decreasing its expression by more than 50% in FL5.12 cells treated with 10 μM of an antisense oligonucleotide for 48 h. This change in FLAP was not accompanied by any increase in apoptosis. Furthermore, FLAP-depleted cells exhibited the same level of apoptosis 8 h after treatment with 10 μM MK886, as did control cells. The increased fluorescence seen in MK886-treated cells loaded with carboxydichlorofluorescein indicates that oxidative reactions are stimulated by this compound, possibly via the release of fatty acids from fatty acid-binding proteins and their subsequent oxidation.
The 5-lipoxygenase-activating protein (FLAP) inhibitor, MK886, induces apoptosis independently of FLAP
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Kaushik DATTA, Shyam S. BISWAL, James P. KEHRER; The 5-lipoxygenase-activating protein (FLAP) inhibitor, MK886, induces apoptosis independently of FLAP. Biochem J 1 June 1999; 340 (2): 371–375. doi: https://doi.org/10.1042/bj3400371
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