Cleavage of focal adhesion proteins and PKCdelta during lovastatin-induced apoptosis in spontaneously immortalized rat brain neuroblasts.
We have previously shown that lovastatin induces apoptosis in spontaneously immortalized rat brain neuroblasts. Focal adhesion proteins and protein kinase Cdelta (PKCdelta) have been implicated in the regulation of apoptosis. We found that lovastatin exposure induced focal adhesion kinase, Crk-associated substrate (p130(Cas)), PKCdelta cleavage and caspase-3 activation in a concentration-dependent manner. Lovastatin effects were fully prevented by mevalonate. The cleavage of p130(Cas) was almost completely inhibited by z-DEVD-fmk, a specific caspase-3 inhibitor, and z-VAD-fmk, a broad spectrum caspase inhibitor, indicating that cleavage is mediated by caspase-3. In contrast, the lovastatin-induced cleavage of PKCdelta was only blocked by z-VAD-fmk suggesting that PKCdelta cleavage is caspase-dependent but caspase-3-independent. Additionally, z-VAD-fmk partially prevented lovastatin-induced neuroblast apoptosis. The present data show that lovastatin may induce neuroblast apoptosis by both caspase-dependent and independent pathways. These findings may suggest that the caspase-dependent component leading to the neuroblast cell death is likely to involve the cleavage of focal adhesion proteins and PKCdelta, which may be partially responsible for some biochemical features of neuroblast apoptosis induced by lovastatin.
González-Fernández
Lauro
L
Departamento de Fisiología, Facultad de Veterinaria, Universidad de Extremadura, Caceres, Spain.
Cerezo-Guisado
Maria Isabel
MI
Langmesser
Sonja
S
Bragado
Maria Julia
MJ
Lorenzo
Maria Jesús
MJ
García-Marín
Luis Jesús
LJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats / Q000378:metabolism*; D013997:Time Factors
D061945:Caspase Inhibitors; D008148:Lovastatin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051745:Protein Kinase C-delta; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D008798:Mevalonic Acid