%0 Journal Article %A Jürgen E. Gschwend %A William R. Fair %A C. Thomas Powell %T Bryostatin 1 Induces Prolonged Activation of Extracellular Regulated Protein Kinases in and Apoptosis of LNCaP Human Prostate Cancer Cells Overexpressing Protein Kinase Cα %D 2000 %J Molecular Pharmacology %P 1224-1234 %V 57 %N 6 %X Previously, we reported that 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced apoptosis of LNCaP human prostate cancer cells was accompanied by prolonged translocation of protein kinase C (PKC)α to non-nuclear membranes and that TPA-resistant LNCaP cells had down-regulated PKCα. Here we show that 10 nM bryostatin 1 induced transient membrane translocation and down-regulation of PKCα, prolonged translocation of PKCδ and ε to non-nuclear membranes, and did not induce cell death but blocked TPA-induced apoptosis. To test the hypothesis that inhibition of TPA-induced apoptosis by bryostatin 1 was due to down-regulation of PKCα, we inducibly overexpressed PKCα in LNCaP cells. Overexpression of PKCα alone did not induce apoptosis, even in clones that contained much more membrane-bound, active PKCα than was observed in TPA-treated untransfected LNCaP cells. However, the addition of 10 nM bryostatin 1 to PKCα-overexpressing LNCaP cells did not yield down-regulation of PKCα and induced extensive apoptosis. Immunoblot analysis revealed that TPA induced prolonged hyperphosphorylation of Raf-1 and activation of extracellular-regulated/mitogen-activated protein kinases 1 and 2 in untransfected LNCaP cells, as did bryostatin 1 in PKCα-overexpressing cells. On the other hand, bryostatin 1 induced only transient hyperphosphorylation of Raf-1 and activation of extracellular-regulated/mitogen-activated protein kinases 1 and 2 in untransfected LNCaP cells. These results confirm a role of prolonged membrane-associated PKCα in PKC activator-mediated LNCaP apoptosis and suggest involvement of the mitogen-activated protein kinase pathway. The American Society for Pharmacology and Experimental Therapeutics %U https://molpharm.aspetjournals.org/content/molpharm/57/6/1224.full.pdf