TY - JOUR
T1 - Involvement of tyrosine phosphorylation in HMG-CoA reductase inhibitor-induced cell death in L6 myoblasts
AU - Mutoh, Tatsuro
AU - Kumano, Takanori
AU - Nakagawa, Hiroto
AU - Kuriyama, Masaru
N1 - Funding Information:
We thank Sankyo Pharmaceutical Co. Ltd. for the generous gift of HCRIs, simvastatin and pravastatin. We also thank Dr. Gordon Guroff (National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA) for his critical reading of the manuscript. We thank Miss Hisayo Hayashi for her excellent technical assistance in this work. This work was supported in part by a grant from the Ministry of Education, Science, and Culture of Japan to T.M.
PY - 1999/2/5
Y1 - 1999/2/5
N2 - 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.
AB - 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.
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U2 - 10.1016/S0014-5793(99)00031-9
DO - 10.1016/S0014-5793(99)00031-9
M3 - Article
C2 - 10037153
AN - SCOPUS:0033003886
SN - 0014-5793
VL - 444
SP - 85
EP - 89
JO - FEBS Letters
JF - FEBS Letters
IS - 1
ER -