Monoterpenes against glioma

Alterations in Ras-mediated signal transduction emerged as a central step in the molecular pathogenesis of high-grade glioblastoma multiforme (GBM). Prenylation of H-Ras by farnesylpyrophosphate (FPP) is required for membrane insertion and facilitated by farnesyltransferase (FTase). FPP is derived from mevalonate, whose production is catalyzed by HMG-CoA reductase (HMGR), which is the rate limiting step of the mevalonate/isoprenoid/cholesterol-(MVA) pathway. Post-translational modification of H-Ras is essential for its oncogenic function, e.g. the stimulation of the mitogen-activated protein kinase (MAPK) pathway. A straight forward prediction from HMGR inhibitor studies would be that FPP levels could be diminished by lovastatin. This assumption, however, has not been tested, and the lack of such data is in stark contrast to the important role of isoprenoids in protein prenylation and oncogenic function. Here, we examine the effects of lovastatin (LOV) and perillyl alcohol (POH) in human malignant astrocytoma cell lines U87 and U343. Human astrocytes (HA) served as controls. Paramters under investigation: Levels of H-Ras, Rac1, RhoA and cdc42 in cell homogenate, cytosolic and membrane fractions, cellular levels of FPP, GGPP and cholesterol, levels of pERK1/2 and ERK1/2, cell proliferation, migration and invasion. The project is carried out by Ph.D. student Sarah Afshordel.

References

Afshordel S, Kern B, Clasohm J, König H, Priester M, Weissenberger J, Kögel D, Eckert GP
Lovastatin and Perillyl alcohol Inhibit Glioma Cell Invasion, Migration, and Proliferation – Impact of Ras-/Rho- Prenylation
Pharmacol Res. 2015, 91:69-77

© Prof. Dr. Gunter P. Eckert 2018