ARACHIDONIC-ACID AS A MEDIATOR OF SOME OF THE ACTIONS OF PHORBOLMYRISTATE ACETATE, A TUMOR PROMOTER AND INDUCER OF DIFFERENTIATION

Phorbolmyristate acetate or 12-0-tetradecanyl phorbol 13-acetate (PMA or TPA) stimulates membrane phospholipases (phospholipase C or A2) resulting in the formation of diacylglyceride, free arachidonic acid, and increased amounts of arachidonic acid metabolites. Both PMA and AA are stimulators of the respiratory burst in phagocytic cells, induce inflammation, cause chromosomal aberrations, have anti-viral activity and activate protein kinase C. The initial action of PMA is on the cell membrane and is concentrated largely in the lipid phase of cell membranes. This evidence suggests that the actions of PMA are in large part mediated by AA, released from the cell membrane lipid pool. Thus, it is likely that the ability of PMA to induce terminal differentiation in HL-60 cells and to suppress C-myc mRNA levels are also mediated by AA and/or its products. This may have relevance to the possible role of AA in the regulation of oncogenes and cancer.