Lovastatin induces apoptosis of spontaneously immortalized rat brain neuroblasts: involvement of nonsterol isoprenoid biosynthesis inhibition.
We have examined the effects of lovastatin and pravastatin (competitive HMG-CoA reductase inhibitors) on the growth and survival of rat brain neuroblasts. Lovastatin, but not pravastatin, suppressed cell growth by inducing apoptosis of neuroblasts in a dose- and time-dependent manner. Apoptosis was accompanied by a decrease in both Bcl-2 and Bcl-xL protein levels, suggesting that changes in the expression of these genes may contribute to apoptosis following lovastatin treatment. Lovastatin treatment was also associated with decreased prenylation of both Ras and Rho A proteins whereas Rac 1 geranylgeranylation was not affected. Lovastatin effects were fully prevented by mevalonate. The present data suggest that lovastatin induces apoptosis of rat brain neuroblasts by its capacity to decrease the prenylation of specific proteins involved in signal transduction pathways that control growth and survival of neuronal cells.
García-Román
N
N
Departamento de Bioquímica y Biología Molecular, Departamento de Fisiología, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain.
Alvarez
A M
AM
Toro
M J
MJ
Montes
A
A
Lorenzo
M J
MJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis*; D017035:Pravastatin / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D012717:Sesquiterpenes; D013185:Squalene / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
D000924:Anticholesteremic Agents; C494821:Bad protein, rat; C494813:Bcl2l1 protein, rat; D002352:Carrier Proteins; D011106:Polyisoprenyl Phosphates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012717:Sesquiterpenes; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C004808:farnesyl pyrophosphate; D013185:Squalene; D002784:Cholesterol; D008148:Lovastatin; D017035:Pravastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid