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  • Title: Differential effects of protein kinase C agonists on prostaglandin production and growth in human breast cancer cells.
    Author: Boorne AJ, Donnelly N, Schrey MP.
    Journal: Breast Cancer Res Treat; 1998 Mar; 48(2):117-24. PubMed ID: 9596483.
    Abstract:
    A regulatory role for protein kinase C (PKC) and eicosanoids has been implicated in the control of breast cancer cell growth and function. Here we report on the effects of the two PKC agonists 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and bryostatin 1 on arachidonic acid metabolism, prostaglandin E2 (PGE2) production, and growth in MDA MB 231 human breast cancer cells. TPA caused a dose-dependent increase in PGE2 production which was maximal at 100 nM and which was blocked in the presence of an equimolar concentration of bryostatin 1. Bryostatin 1 alone had no effect on PGE2 synthesis. Both TPA and bryostatin 1 stimulated arachidonic acid release and reduced fatty acid incorporation into phosphatidylinositol, their combined effect being less than additive in co-incubation. Interleukin-1beta (IL-1beta) induced a tenfold and twofold synergistic increase in PGE2 production in the presence of TPA (10 nM) and bryostatin 1 (10 nM) respectively. Bryostatin 1 caused a dose-dependent inhibition of the phorbol ester-potentiated IL-1beta response. Treatment of MDA MB 231 cells for 4 days with TPA (10 nM) or bryostatin 1 (10 nM) inhibited cell growth by 74% and 20% respectively. Co-treatment with both PKC agonists reversed the anti-proliferative effect of TPA to that seen with bryostatin 1 alone. In contrast the anti-proliferative action of ceramide, another PKC modulator, was unaffected in the presence of bryostatin 1. TPA also induced morphological changes in MDA MB 231 cells which were prevented by co-treatment with bryostatin 1. This study further supports a regulatory role for PKC in the control of eicosanoid synthesis and growth in human breast cancer cells. Although the findings are consistent with bryostatin 1 acting as an antagonist/weak agonist in relation to TPA action, the mechanistic basis for this differential action of TPA and bryostatin 1 is uncertain.
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