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Inhibition of farnesylation blocks growth but not differentiation in FRTL-5 thyroid cells
M Bifulco1, C Laezza, S M Aloj
1Centro di Endocrinologia ed Oncologia Sperimentale G. Salvatore del CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Università di Napoli Federico II, Naples, Italy.
Abstract:
The cholesterol lowering drug lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, blocks DNA synthesis and proliferation of thyrotropin (TSH) primed FRTL-5 rat thyroid cells. The blockade can be completely prevented and/or reversed by mevalonate and largely prevented and/or reversed by farnesol whereas cholesterol and/or other non-sterol mevalonate derivatives such as ubiquinone, dolichol or isopentenyladenosine are ineffective. TSH-dependent augmentation of cyclic-AMP and cAMP dependent differentiated functions, such as iodide uptake, are unaffected by lovastatin. 3H-Thymidine incorporation into DNA is also decreased by alpha-hydroxyfarnesyl-phosphonic acid, an inhibitor of protein farnesylation which mimicks the effect of lovastatin since it also leaves unaffected TSH stimulated iodide uptake. It is suggested that the HMG-CoA reductase inhibitor lovastatin affects cell proliferation mainly through inhibition of protein farnesylation which results in altered function proteins relevant for proliferation control, notably p21ras and/or other small GTPases.
Insights
Lovastatin, a cholesterol drug, inhibits thyroid cell proliferation by blocking DNA synthesis. This effect is reversed by mevalonate and farnesol, suggesting protein farnesylation is key.
Area of Science:
- Cell Biology
- Molecular Biology
- Endocrinology
Background:
- Thyrotropin (TSH) primes FRTL-5 rat thyroid cells for proliferation.
- Lovastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.
Purpose of the Study:
- To investigate the mechanism by which lovastatin affects thyroid cell proliferation.
- To determine the role of mevalonate pathway intermediates in lovastatin's effects.
Main Methods:
- FRTL-5 rat thyroid cells were treated with lovastatin.
- Cell proliferation and DNA synthesis were measured.
- Effects of mevalonate, farnesol, cholesterol, and other derivatives were assessed.
- TSH-stimulated functions like iodide uptake were monitored.
Main Results:
- Lovastatin blocked DNA synthesis and proliferation in TSH-primed FRTL-5 cells.
- Mevalonate and farnesol prevented/reversed lovastatin's blockade.
- Cholesterol and other non-sterol derivatives were ineffective.
- TSH-dependent cyclic-AMP augmentation and differentiated functions (iodide uptake) were unaffected by lovastatin.
- Alpha-hydroxyfarnesyl-phosphonic acid, a protein farnesylation inhibitor, mimicked lovastatin's effect on proliferation but not on iodide uptake.
Conclusions:
- Lovastatin inhibits thyroid cell proliferation primarily by blocking protein farnesylation.
- This inhibition affects proteins like p21ras and other small GTPases involved in proliferation control.
- Lovastatin's effects on proliferation are distinct from its effects on differentiated functions like iodide uptake.