Lovastatin-induced PC-12 cell differentiation is associated with RhoA/RhoA kinase pathway inactivation.
Relatively little is known about the relationship between cellular lipid composition and the ability of neuroblasts to elaborate axonal and dendritic processes. We have studied the role of cholesterol and non-sterol isoprenoids during neurite outgrowth in PC-12 cells using inhibitors of cholesterol biosynthesis that act at different points in the biosynthetic pathway. We provide evidence that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase leads to extensive, sterol-dependent neurite outgrowth, via a mechanism that is independent of the requirement for sterols during proliferation. This effect is prevented by non-sterol mevalonate derivatives, suggesting the involvement of protein prenylation in the regulation of neurite outgrowth. Furthermore, we show that lovastatin inhibits both RhoA activation and Cofilin phosphorylation, while geranylgeraniol reverses these effects. Finally, the effect of geranylgeraniol on neurite outgrowth is prevented by Y-27632, an inhibitor of RhoA kinase. Taken together, our results suggest that inhibition of geranylgeraniol synthesis causes sterol-dependent neurite outgrowth in a process that is mediated by inhibition of RhoA signaling.
Fernández-Hernando
Carlos
C
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Madrid, Spain.
Suárez
Yajaira
Y
Lasunción
Miguel A
MA
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002784:Cholesterol / Q000096:biosynthesis; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008148:Lovastatin / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D013261:Sterols / Q000096:biosynthesis*; D013729:Terpenes / Q000378:metabolism*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism*
D004224:Diterpenes; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D013261:Sterols; D013729:Terpenes; D002784:Cholesterol; D008148:Lovastatin; C017338:geranylgeraniol; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein