Involvement of tyrosine phosphorylation in HMG-CoA reductase inhibitor-induced cell death in L6 myoblasts.
Our previous studies have shown that the HMG-CoA reductase (HCR) inhibitor (HCRI), simvastatin, causes myopathy in rabbits and kills L6 myoblasts. The present study was designed to elucidate the molecular mechanism of HCRI-induced cell death. We have demonstrated that simvastatin induces the tyrosine phosphorylation of several cellular proteins within 10 min. These phosphorylations were followed by apoptosis, as evidenced by the occurrence of internucleosomal DNA fragmentation and by morphological changes detected with Nomarski optics. Simvastatin-induced cell death was prevented by tyrosine kinase inhibitors. The MTT assay revealed that the addition of mevalonic acid into the culture medium partially inhibited simvastatin-induced cell death. Thus, these results suggested that protein tyrosine phosphorylation might play an important role in the intracellular signal transduction pathway mediating the HCRI-induced death of myoblasts.
The 2nd Department of Internal Medicine, Faculty of Medicine, Fukui Medical University, Japan. mutoh@fmsrsa.fukui-med.ac.jp
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Kumano
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Nakagawa
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Kuriyama
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D047029:Lactams, Macrocyclic; D008798:Mevalonic Acid / Q000494:pharmacology; D008970:Molecular Weight; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013997:Time Factors
D016227:Benzoquinones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; D019000:Phosphotyrosine; C020754:herbimycin; D019821:Simvastatin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; D017035:Pravastatin; D008798:Mevalonic Acid