Manipulation of the mevalonate pathway in glial‐derived cells

Intermediates in the mevalonate pathway are critical for cell growth and survival. Statin‐induced inhibition of hydroxymethylglutaryl coenzyme A reductase prevents the formation of mevalonate and its derivatives, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These isoprenoids post‐translationally modify signal transduction proteins. Glial (C6) and glioblastoma (A172) cells were incubated with 0.1 – 10 μM lovastatin without and with 10 μM mevalonate, FPP, or GGPP for 24 hours. Lovastatin alters RAS expression in A172, but not C6 cells. In both lines unmodified RAP1A does accumulate in a dose‐dependent manner from 1 – 10 μM lovastatin. The addition of GGPP, but not FPP, prevents this effect. Rheb protein levels increase with 10 μM lovastatin. This increase is enhanced with 10 μM GGPP. Selective inhibition of geranylgeranyl (10 μM GGTI‐286), but not farnesyl protein transferase (10 μM FTI‐277) results in an upregulation of Rheb in A172 but not C6 cells. The basis for these differences may lie in distinct regulation for the mevalonate pathway between these cell lines. Ongoing investigations will determine this regulatory difference.