Lovastatin inhibits Rho-regulated expression of E-selectin by TNFalpha and attenuates tumor cell adhesion.
E-selectin mediated cell-cell adhesion plays an important role in inflammatory processes and extravasation of tumor cells. Tumor necrosis factor-alpha (TNF-alpha) induces E-selectin gene and protein expression in primary human endothelial cells (HUVEC) and in an endothelial cell line (EA.hy-926). As shown by ELISA and FACS analyses, HMG-CoA reductase inhibitors (e.g., lovastatin) impair the TNF-alpha stimulated increase in E-selectin protein expression. Similar results were obtained for E-selectin mRNA expression and promoter activity, indicating that the effect of lovastatin is based on inhibition of gene expression. The effective inhibitory concentration of lovastatin was in a physiologically relevant range (IC50<0.1 microM). Lovastatin-mediated block of TNF-alpha induced E-selectin expression is due to inhibition of protein geranylgeranylation rather than farnesylation. Down-regulation of Rho signaling by coexpression of dominant-negative Rho mutants (i.e RhoA, RhoB and Rac) impaired TNF-alpha driven E-selectin gene expression, indicating Rho signaling to be essential for transcriptional activation of the E-selectin gene. Inhibition of E-selectin expression by lovastatin gives rise to a significant reduction in TNF-alpha stimulated adhesion of colon carcinoma cells to HUVEC. Furthermore, low concentration of lovastatin (i.e., < or =1 microM) attenuated TNF-alpha induced tumor cell invasion in vitro. The data support the view that statins might be clinically useful in protection against E-selectin mediated metastasis.
Nübel
Tobias
T
University of Mainz, Institute of Toxicology, Division of Applied Toxicology, Mainz, Germany.
Dippold
Wolfgang
W
Kleinert
Hartmut
H
Kaina
Bernd
B
Fritz
Gerhard
G
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D019040:E-Selectin / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D019040:E-Selectin; D014409:Tumor Necrosis Factor-alpha; D008148:Lovastatin; D020741:rho GTP-Binding Proteins