The mechanism of skin tumor promotion caused by phorbol esters: possible involvement of arachidonic acid cascade/lipoxygenase, protein kinase C and calcium/calmodulin systems.
12-O-Tetradecanoylphorbol-13-acetate (TPA) has been used as a potent tumor promoter in mouse skin. The mechanisms of TPA actions were studied by using several types of inhibitors. TPA-caused responses in mouse skin such as skin tumor promotion, epidermal ornithine decarboxylase (ODC) induction and skin inflammation were inhibited by various lipoxygenase inhibitors of the arachidonic acid cascade. Lipoxygenase inhibitors also inhibited TPA-caused ODC induction in isolated epidermal cells or cultured epidermal cells. Therefore, it is possible that these drugs inhibit TPA-caused ODC induction in mouse skin by directly acting on epidermal cells. TPA actions were also inhibited by either protein kinase C inhibitors, calmodulin antagonists or calcium blockers. These results suggest that arachidonic acid/lipoxygenase, protein kinase C and calcium-calmodulin systems play essential roles in the mechanism of tumor promotion by TPA.
Nakadate
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Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002118:Calcium / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology*; D008084:Lipoxygenase / Q000502:physiology*; D051379:Mice; D011493:Protein Kinase C / Q000502:physiology*; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism*
D001095:Arachidonic Acids; D002147:Calmodulin; D016718:Arachidonic Acid; D008084:Lipoxygenase; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium