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Forschungsdatenbank PMU-SQQUID

Simvastatin inhibits malignant transformation following expression of the Ha-ras oncogene in NIH 3T3 fibroblasts.
Fürst, J; Haller, T; Chwatal, S; Wöll, E; Dartsch, PC; Gschwentner, M; Dienstl, A; Zwierzina, H; Lang, F; Paulmichl, M; Ritter, M;
Cell Physiol Biochem. 2002; 12(1): 19-30.
Originalarbeiten (Zeitschrift)


Paulmichl Markus
Ritter Markus


In previous studies we have shown that the expression of the transforming Ha-ras oncogene in NIH 3T3 fibroblasts stimulates cellular calcium entry, which triggers oscillatory calcium induced calcium release from internal stores. The intracellular calcium oscillations lead to cytoskeletal remodeling by actin stress fiber depolymerization and activation of the Na(+)/H(+) exchanger thus mediating cell swelling and intracellular alkalosis, both important mitogenic signals. This is evidenced by abrogation of Ha-ras induced growth factor independent cell proliferation by interference with any of these events, i.e. by inhibition of cellular calcium entry or inhibition of the Na(+)/H(+) exchanger. As shown in this study, simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme for cholesterol biosynthesis, is able to prevent these events following the expression of the transforming Ha-ras oncogene. We show, that simvastatin inhibits farnesylation dependent membrane translocation of a CAAX motive bearing yellow fluorescent protein and suppresses Ha-ras stimulated cellular calcium influx, which can be identified as capacitative calcium entry. In addition simvastatin is able to block regulatory volume decrease channels and to suppress the cytoskeletal remodeling, intracellular alkalinization, increase in cell volume and growth factor independent cell proliferation induced by the oncogene. Thus simvastatin is able to prevent crucial cellular events following expression of the transforming Ha-ras oncogene.

Useful keywords (using NLM MeSH Indexing)

3T3 Cells



Bacterial Proteins/genetics


Cell Division/drug effects

Cell Membrane/metabolism

Cell Size/drug effects

Cell Size/physiology

Cell Transformation, Neoplastic/drug effects*

Cytoskeleton/drug effects


Fibroblasts/drug effects*


Gene Expression

Genes, ras/physiology*

Hydrogen-Ion Concentration

Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology*

Intracellular Fluid/metabolism

Ion Channels/drug effects

Luminescent Proteins/genetics


Patch-Clamp Techniques

Protein Prenylation/physiology

Protein Transport/physiology

Recombinant Fusion Proteins/genetics

Recombinant Fusion Proteins/metabolism



Find related publications in this database (Keywords)

Ha-ras oncogene
actin filaments
cell volume
cell proliferation
intracellular pH
protein farnesylation
capacitative calcium entry