HMG-COA REDUCTASE INHIBITOR-INDUCED L6 MYOBLAST CELL-DEATH - INVOLVEMENT OF THE PHOSPHATIDYLINOSITOL 3-KINASE PATHWAY

Our previous studies have shown that the HMG-CoA reductase inhibitor ( HCRI) causes rhabdomyolysis and electrical myotonia in rabbits and als o 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 prote ins and therefore induced translocation of a significant part of Ras p roteins from the membrane fraction into the cytosolic fraction within 10 min. With this translocation, PI 3-kinase activity of the Ras-hound form both in total and in the membrane fraction was also decreased pr ofoundly. Furthermore, various PI 3-kinase inhibitors also caused cell death with morphological changes similar to those caused by simvastat in. These results might represent the molecular events of HCRI-induced cell death, and suggest the significance of PI 3-kinase activity of t he Ras-hound form in the maintenance of cell viability. (C) 1998 Feder ation of European Biochemical Societies.