LACK OF CORRELATION BETWEEN 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE-ACTIVITY AND LOVASTATIN RESISTANCE IN NERVE GROWTH-FACTOR TREATED PC-12 CELLS

1. The relationships among the mevalonic acid (MVA) forming enzyme, 3- hydroxy-3-methylglutaryl coenzyme A (CoA) reductase, cell growth and d ifferentiation, and the cytotoxic effects of the reductase inhibitor l ovastatin were studied in PC-12 cells, exposed to growth factors. 2. W hen added individually, nerve growth factor (NGF), basic fibroblast gr owth factor, and epidermal growth factor induce an increase in HMG-CoA reductase activity in cells grown in serum-containing medium. In the presence of serum, the effect of NGF on HMG-CoA reductase is persisten t. 3. Short-term serum starvation and long-term NGF treatment, in comb ination, have an additive effect, resulting in a high reductase activi ty. 4. Unlike serum and MVA, which downregulate levels of HMG-CoA redu ctase by accelerating its degradation, NGF upregulates reductase by sl owing the rate of its degradation. This mechanism, however, appears to operate only in the presence of serum, as after prolonged growth with NGF in serum-free medium, cells have a low reductase activity. 5. PC- 12 cells grown in the absence of NGF are highly sensitive to lovastati n (25 mu M) and more than 70% of the cells die after 48 hr. NGF confer s lovastatin resistance on cells grown in the presence or in the absen ce of serum (only 30-40% cell death after 48 hr with lovastatin). 6. N GF-induced resistance on lovastatin develops with time and is apparent only in the well-differentiated PC-12 cells whether or not the cells express a high reductase activity. 7. Thus, levels of HMG-CoA reductas e activity and lovastatin resistance in PC-12 cells are not directly c orrelated, though clearly inversed lovastatin cytotoxicity and elevate d reductase activities are expressed during the period of cell prolife ration. 8. These data suggest that fully differentiated neuronal cells may not be affected by prolonged high doses of lovastatin.