TY - JOUR
T1 - HMG-CoA reductase inhibitor-induced L6 myoblast cell death
T2 - Involvement of the phosphatidylinositol 3-kinase pathway
AU - Nakagawa, Hiroto
AU - Mutoh, Tatsuro
AU - Kumano, Takanori
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. Keiichi Nakahara (The Third Department of Internal Medicine, Kagoshima University School of Medicine, Kagoshima, Japan) for providing L6 myoblasts and sharing information on HCRI with us. This work was supported in part by the Ministry of Education, Science, and Culture of Japan to T.M.
PY - 1998/11/6
Y1 - 1998/11/6
N2 - Our previous studies have shown that the HMG-CoA reductase inhibitor (HCRI) causes rhabdomyolysis and electrical myotonia in rabbits and also kills L6 myoblasts in culture. In the present study, we analyzed the intracellular signal transduction pathway of HCRI-induced cell death using L6 myoblasts as a model system. Here, we report that simvastatin, a lipophilic HCRI, efficiently inhibited isoprenylation of Ras proteins and therefore induced translocation of a significant part of Ras proteins from the membrane fraction into the cytosolic fraction within 10 min. With this translocation, PI 3-kinase activity of the Ras-bound form both in total and in the membrane fraction was also decreased profoundly. Furthermore, various PI 3-kinase inhibitors also caused cell death with morphological changes similar to those caused by simvastatin. These results might represent the molecular events of HCRI-induced cell death, and suggest the significance of PI 3-kinase activity of the Ras-bound form in the maintenance of cell viability. Copyright (C) 1998 Federation of European Biochemical Societies.
AB - Our previous studies have shown that the HMG-CoA reductase inhibitor (HCRI) causes rhabdomyolysis and electrical myotonia in rabbits and also kills L6 myoblasts in culture. In the present study, we analyzed the intracellular signal transduction pathway of HCRI-induced cell death using L6 myoblasts as a model system. Here, we report that simvastatin, a lipophilic HCRI, efficiently inhibited isoprenylation of Ras proteins and therefore induced translocation of a significant part of Ras proteins from the membrane fraction into the cytosolic fraction within 10 min. With this translocation, PI 3-kinase activity of the Ras-bound form both in total and in the membrane fraction was also decreased profoundly. Furthermore, various PI 3-kinase inhibitors also caused cell death with morphological changes similar to those caused by simvastatin. These results might represent the molecular events of HCRI-induced cell death, and suggest the significance of PI 3-kinase activity of the Ras-bound form in the maintenance of cell viability. Copyright (C) 1998 Federation of European Biochemical Societies.
UR - https://www.scopus.com/pages/publications/0031793819
UR - https://www.scopus.com/pages/publications/0031793819#tab=citedBy
U2 - 10.1016/S0014-5793(98)01320-9
DO - 10.1016/S0014-5793(98)01320-9
M3 - Article
C2 - 9827563
AN - SCOPUS:0031793819
SN - 0014-5793
VL - 438
SP - 289
EP - 292
JO - FEBS Letters
JF - FEBS Letters
IS - 3
ER -