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Lovastatin inhibits the extracellular-signal-regulated kinase pathway in immortalized rat brain neuroblasts
Maria Isabel Cerezo-Guisado1, Natalia García-Román, Luis Jesús García-Marín
1Departamento de Bioquímica, Biología Molecular y Genética Universidad de Extremadura, E-10071 Cáceres, Spain.
Abstract:
We have shown previously that lovastatin, a 3-hydroxy-3-methyl- glutaryl coenzyme A reductase inhibitor, induces apoptosis in spontaneously immortalized rat brain neuroblasts. In the present study, we analysed the intracellular signal transduction pathways by which lovastatin induces neuroblast apoptosis. We showed that lovastatin efficiently inhibited Ras activation, which was associated with a significant decrease in ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation. Lovastatin also decreased CREB phosphorylation and CREB-mediated gene expression. The effects of lovastatin on the Ras/ERK1/2/CREB pathway were time- and concentration-dependent and fully prevented by mevalonate. In addition, we showed that two MEK [MAPK (mitogen-activated protein kinase)/ERK kinase] inhibitors, PD98059 and PD184352, were poor inducers of apoptosis in serum-treated neuroblasts. However, these inhibitors significantly increased apoptosis induced by lovastatin treatment. Furthermore, we showed that pharmacological inhibition of both MEK and phosphoinositide 3-kinase activities was able to induce neuroblast apoptosis with similar efficacy as lovastatin. Our results suggest that lovastatin triggers neuroblast apoptosis by regulating several signalling pathways, including the Ras/ERK1/2 pathway. These findings might also contribute to elucidate the intracellular mechanisms involved in the central nervous system side effects associated with statin therapy.
Insights
Lovastatin induces neuroblast apoptosis by inhibiting the Ras/ERK1/2 pathway and affecting CREB phosphorylation. These findings may explain statin-related central nervous system side effects.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Lovastatin, a HMG-CoA reductase inhibitor, previously shown to induce apoptosis in rat brain neuroblasts.
- Understanding the specific intracellular signaling pathways involved in lovastatin-induced neuroblast apoptosis is crucial.
Purpose of the Study:
- To analyze the intracellular signal transduction pathways mediating lovastatin-induced neuroblast apoptosis.
- To investigate the role of the Ras/ERK1/2/CREB pathway in this process.
Main Methods:
- Assessed Ras activation and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation.
- Measured cAMP response element-binding protein (CREB) phosphorylation and gene expression.
- Utilized MEK (MAPK/ERK kinase) inhibitors (PD98059, PD184352) and phosphoinositide 3-kinase inhibition.
Main Results:
- Lovastatin inhibited Ras activation and decreased ERK1/2 phosphorylation and CREB phosphorylation.
- The effects were time- and concentration-dependent and reversible by mevalonate.
- MEK inhibitors enhanced lovastatin-induced apoptosis, and combined MEK/PI3K inhibition mimicked lovastatin's apoptotic effect.
Conclusions:
- Lovastatin triggers neuroblast apoptosis via multiple signaling pathways, including the Ras/ERK1/2 pathway.
- Findings may elucidate mechanisms behind statin-associated central nervous system side effects.
