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Cellular and Molecular Neurobiology

, Volume 14, Issue 2, pp 119–132 | Cite as

Lack of correlation between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and lovastatin resistance in nerve growth factor treated PC-12 cells

  • Michal Marom
  • Gilad Ben-Baruch
  • Joseph Roitelman
  • Yoel Kloog
Article

Summary

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 µM) 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.

7. Thus, levels of HMG-CoA reductase activity and lovastatin resistance in PC-12 cells are not directly correlated, though clearly inversed lovastatin cytotoxicity and elevated reductase activities are expressed during the period of cell proliferation.

8. These data suggest that fully differentiated neuronal cells may not be affected by prolonged high doses of lovastatin.

Key words

PC12 nerve growth factor 3-hydroxy-3-methylglutaryl coenzyme reductase lovastatin 

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Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Michal Marom
    • 1
  • Gilad Ben-Baruch
    • 2
  • Joseph Roitelman
    • 3
  • Yoel Kloog
    • 1
  1. 1.Department of Biochemistry, The George S. Wise Faculty of Life SciencesTel Aviv UniversityTel AvivIsrael
  2. 2.Department of Obstetrics and Gynecology, Meir Hospital, Kfar Saba, and Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.The Institute of Lipid and Atherosclerosis ResearchSheba Medical CenterTel HashomerIsrael

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