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Lovastatin is a Potent Inhibitor of Meningioma Cell Proliferation: Evidence for Inhibition of a Mitogen Associated Protein Kinase

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Abstract

Lovastatin inhibits 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase the rate limiting enzyme for synthesis of mevalonic acid, a precursor for cholesterol, farnesyl and geranylgeranyl pyrophosphate isoprenoids. Recent studies suggest it also has growth inhibitory properties. Posttranslational farnesyl or geranylgeranylation of low molecular weight GTP-binding proteins such as RAS and RHO are thought to be an essential step in activation of phosphorylation cascades such as the RAS–RAF-1–MEK-1–MAPK/ERK pathway which stimulate cell proliferation. In this study, we evaluated lovastatin effects on meningioma cell proliferation and activation of the MEK-1–MAPK/ERK pathway.

The effect of lovastatin on cell proliferation was assessed in eight human meningioma cell cultures stimulated by platelet derived growth factor (PDGF)-BB, cerebrospinal fluid (CSF), and fetal bovine serum (FBS). Concomitant lovastatin effects on phosphorylation/activation of mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) kinase (MEK-1) and MAPK/ERK were assessed by Western blot. Whether lovastatin acts via a mevalonate-dependent mechanism was also evaluated.

Coadministration of lovastatin completely blocked PDGF-BB, CSF, and FBS stimulation of [3H]-thymidine incorporation and cell proliferation. Lovastatin inhibited PDGF-BB's stimulatory effect in a dose dependent manner. Concomitant with its growth inhibitory effects, lovastatin reduced phosphorylation/activation of MEK-1/2 in five meningiomas and MAPK/ERK in seven. Coadministration of mevalonate with lovastatin partially restored PDGF's mitogenic effect.

Lovastatin is a potent inhibitor of meningioma cell proliferation which may act in part by reducing activation of MEK-1–MAPK/ERK pathway. Additional studies are warranted to assess whether lovastatin and similar HMG-CoA reductase inhibitors represent a new adjunctive chemotherapy for recurrent meningiomas.

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Johnson, M.D., Woodard, A., Okediji, E.J. et al. Lovastatin is a Potent Inhibitor of Meningioma Cell Proliferation: Evidence for Inhibition of a Mitogen Associated Protein Kinase. J Neurooncol 56, 133–142 (2002). https://doi.org/10.1023/A:1014588214966

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