Lovastatin effect in rat neuroblasts of the CNS: inhibition of cap-dependent translation

• Published in: Journal of neurochemistry Vol. 106; no. 3; pp. 1078 - 1091
• Main Authors: Santa-Catalina, Marta Olivera, Garcia-Marin, Luis Jesus, Bragado, María Julia
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.08.2008; Blackwell Publishing Ltd; Blackwell
• Subjects: Animals; Apoptosis; Biochemistry; Biological and medical sciences; Cells, Cultured; Central nervous system; Central Nervous System - cytology; Central Nervous System - drug effects; Central Nervous System - physiology; Central neurotransmission. Neuromudulation. Pathways and receptors; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose-Response Relationship, Drug; eIF4G; eukaryotic translation initiation factor 4E-binding protein 1; Fundamental and applied biological sciences. Psychology; Gene expression; lovastatin; Lovastatin - pharmacology; Medical sciences; neuroblasts; Neurology; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Protein Biosynthesis - drug effects; Protein Biosynthesis - physiology; Rats; RNA Cap-Binding Proteins - antagonists & inhibitors; RNA Cap-Binding Proteins - biosynthesis; RNA Cap-Binding Proteins - genetics; Statins; translation; Vertebrates: nervous system and sense organs; eukaryotic translation initiation factor 4E-binding protein 1; Phosphorylation; Rat; Growth; Rodentia; Central nervous system; Biosynthesis; Gene expression; Survival; Encephalon; neuroblasts; Binding protein; Vertebrata; Mammalia; Treatment; elF4G; Protein synthesis; Synaptic plasticity; translation; lovastatin; Apoptosis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05458.x

Mevalonate biosynthesis pathway is important in cell growth and survival and its blockade by 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, statins, arrest brain neuroblasts growth and induce apoptosis. Translation is among the main biochemical mechanisms that controls gene expression and therefore cell growth or apoptosis. In the CNS, translation regulates synaptic plasticity. Thus, our aim was to investigate the effect of lovastatin in protein translation in rat neuroblasts of the CNS and the biochemical pathways involved. Lovastatin treatment in rat brain neuroblasts causes a significant time- and concentration-inhibition of protein synthesis, which is partially mediated by phosphatydilinositol 3-kinase/mammalian target of rapamycin (mTOR) pathway inhibition. Lovastatin treatment decreases the phosphorylation state of mTOR substrates, p70S6K and eukaryotic translation initiation factor (eIF) 4E-binding protein 1 and simultaneously increases eIF4E-binding protein 1 in a time-dependent manner. Concomitantly, lovastatin causes a decrease in eIF4G cellular amount, which is partially mediated by caspase(s) activity excluding caspase 3. These biochemical pathways affected by lovastatin might explain the protein translation inhibition observed in neuroblasts. Cycloheximide treatment, which blocked protein synthesis, does not induce neuroblasts apoptosis. Therefore, we suggest that lovastatin-induced protein synthesis inhibition might not contribute to the concomitant neuroblasts apoptosis previously observed.