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Vol. 57, Issue 6, 1224-1234, June 2000
Urologic Oncology Research Laboratory and George M. O'Brien
Urology Research Center for Prostate Cancer, Memorial Sloan-Kettering
Cancer Center, New York, New York
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)
to non-nuclear
membranes and that TPA-resistant LNCaP cells had down-regulated PKC.
Here we show that 10 nM bryostatin 1 induced transient membrane
translocation and down-regulation of PKC, prolonged translocation of
PKC
and 
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 PKC, we inducibly overexpressed PKC in LNCaP
cells. Overexpression of PKC alone did not induce apoptosis, even in
clones that contained much more membrane-bound, active PKC than was
observed in TPA-treated untransfected LNCaP cells. However, the
addition of 10 nM bryostatin 1 to PKC-overexpressing LNCaP cells did
not yield down-regulation of PKC 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 PKC-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 PKC in PKC activator-mediated LNCaP apoptosis
and suggest involvement of the mitogen-activated protein kinase pathway.
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