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Molecular Pharmacology

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Research ArticleArticle

Bryostatin 1 Induces Prolonged Activation of Extracellular Regulated Protein Kinases in and Apoptosis of LNCaP Human Prostate Cancer Cells Overexpressing Protein Kinase Cα

Jürgen E. Gschwend, William R. Fair and C. Thomas Powell
Molecular Pharmacology June 2000, 57 (6) 1224-1234;
Jürgen E. Gschwend
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William R. Fair
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C. Thomas Powell
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Abstract

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.

Footnotes

  • Send reprint requests to: C. Thomas Powell, Ph.D., Department of Cancer Biology, The Cleveland Clinic Foundation, 9500 Euclid Ave.-ND50, Cleveland, OH 44195.

  • ↵1 Current address: Department of Urology, University of Ulm, 89075 Ulm, Germany.

  • This work was supported in part by National Institutes of Health Grant DK/CA47650. J.E.G. was supported by Deutsche Forschungsgemeinschaft (Bonn, Germany).

  • Abbreviations:
    TPA
    12-O-tetradecanoylphorbol-13-acetate
    ERK
    extracellular-regulated/mitogen-activated protein kinase
    FBS
    fetal bovine serum
    PKC
    protein kinase C
    tet
    tetracycline
    tTA
    tetracycline-repressible transactivator protein
    XTT
    2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt
    • Received September 3, 1999.
    • Accepted February 23, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (6)
Molecular Pharmacology
Vol. 57, Issue 6
1 Jun 2000
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Research ArticleArticle

Bryostatin 1 Induces Prolonged Activation of Extracellular Regulated Protein Kinases in and Apoptosis of LNCaP Human Prostate Cancer Cells Overexpressing Protein Kinase Cα

Jürgen E. Gschwend, William R. Fair and C. Thomas Powell
Molecular Pharmacology June 1, 2000, 57 (6) 1224-1234;

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Research ArticleArticle

Bryostatin 1 Induces Prolonged Activation of Extracellular Regulated Protein Kinases in and Apoptosis of LNCaP Human Prostate Cancer Cells Overexpressing Protein Kinase Cα

Jürgen E. Gschwend, William R. Fair and C. Thomas Powell
Molecular Pharmacology June 1, 2000, 57 (6) 1224-1234;
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