Stimulation of arachidonic acid metabolism in rat peritoneal macrophages by thapsigargin, a non-(12-O-tetradecanoylphorbol-13-acetate) (TPA)-type tumor promoter

The effects of thapsigargin, which is a histamine secretagogue and has recently been found to be a non-(12-O-tetradecanoylphorbol-13-acetate) (TPA)-type tumor promoter in two-stage carcinogenesis using mouse skin, on arachidonic acid metabolism in rat peritoneal macrophages were examined. The release of radioactivity from ³H arachidonic acid-labeled macrophages was increased at doses more than 10 ng/ml. Prostaglandin E₂ production was also increased dose-dependently without inducing prominent changes in cell morphology. The potency to stimulate prostaglandin E₂ production by thapsigargin was stronger than that by TPA at a dose of 10 ng/ml when measured 6 h after the incubation. HPLC analysis revealed that thapsigargin stimulated the production of lipoxygenase products such as leukotriene B₄ and 12-hydroxyeicosatetraenoic acid as well as cyclooxygenase products such as prostaglandin E₂ and 6-ketoprostaglandin F_1α. Thapsigargicin, an analogue of thapsigargin, also stimulated prostaglandin E₂ production. The mechanism of the action of thapsigargin was discussed. It was confirmed that the tumor promoters are associated with the activity to stimulate arachidonic acid metabolism irrespective of their type, TPA-type or non-TPA-type.