Inhibition of 12-O-tetradecanoylphorbol-13-acetate-accelerated phospholipid metabolism by 5,8,11,14-eicosatetraynoic acid.
The tumor-promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA), accelerates choline phospholipid synthesis in bovine lymphocytes by an oxygen-dependent mechanism. This action is prevented by high concentrations of the cyclooxygenase inhibitor, indomethacin (1 to 3 mM), suggesting a possible involvement of lipid oxidation in the response. The acetylenic analog of arachidonic acid, 5,8,11,14-eicosatetraynoic acid (ETYA), at concentrations in the 10 to 50 microM range also prevents the acceleration of the incorporation of [methyl-3H]choline hydrochloride into choline phospholipids, and it appears more selective in its action. This antagonistic effect of ETYA, an agent which inhibits both the cyclooxygenase and lipoxygenase routes of arachidonic acid oxidation, can be precluded by arachidonic acid but not by other unsaturated or saturated fatty acids. If ETYA is added to lymphocyte cultures after 1 hr of TPA treatment, the established rate of [methyl-3H]choline hydrochloride incorporation is unaffected, but further acceleration is blocked. The inhibition by ETYA cannot be counteracted by any of the prostaglandins, Types A, B, D, E, or F alpha, or by the prostacyclin compounds, PGI1 and 6,9-thia-PGI2. The thromboxane pathway also appears not to be involved since 9,11-azoprosta-5,13-dienoic acid (Azo I), a selective inhibitor of thromboxane synthetase, does not affect the TPA response. These results suggest that TPS may activate the lipoxygenase rather than the cyclooxygenase pathway for lipid oxidation and that an arachidonic acid hydroperoxide or a subsequent metabolite plays a key role in the stimulation of choline phospholipid synthesis by the tumor-promoting phorbol ester, TPA.
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002794:Choline / Q000378:metabolism; D011464:Epoprostenol / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D010704:Phorbols / Q000037:antagonists & inhibitors*; D010743:Phospholipids / Q000378:metabolism*; D011453:Prostaglandins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D005231:Fatty Acids, Unsaturated; D010704:Phorbols; D010743:Phospholipids; D011453:Prostaglandins; D015117:5,8,11,14-Eicosatetraynoic Acid; D011464:Epoprostenol; D002794:Choline; D013755:Tetradecanoylphorbol Acetate