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 differentiation, and the cytotoxic effects of the reductase inhibitor lovastatin were studied in PC-12 cells, exposed to growth factors. 2. When added individually, nerve growth factor (NGF), basic fibroblast growth 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 persistent. 3. Short-term serum starvation and long-term NGF treatment, in combination, have an additive effect, resulting in a high reductase activity. 4. Unlike serum and MVA, which downregulate levels of HMG-CoA reductase by accelerating its degradation, NGF upregulates reductase by slowing 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 lovastatin (25 microM) and more than 70% of the cells die after 48 hr. NGF confers lovastatin resistance on cells grown in the presence or in the absence of serum (only 30-40% cell death after 48 hr with lovastatin). 6. NGF-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
M
M
Marom
G
G
Ben-Baruch
J
J
Roitelman
Y
Y
Kloog
D000818:Animals; D001769:Blood; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D015854:Up-Regulation
D009414:Nerve Growth Factors; D016222:Fibroblast Growth Factor 2; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid