Lovastatin inhibits Rho-regulated expression of E-selectin by TNFalpha and attenuates tumor cell adhesion.

Abstract

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.

• Authors: Tobias Nübel, Wolfgang Dippold, Hartmut Kleinert, Bernd Kaina, Gerhard Fritz
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 18 Issue 1 Pg. 140-2 (Jan 2004) ISSN: 1530-6860 [Electronic] United States
• PMID: 14630701 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• E-Selectin
• Tumor Necrosis Factor-alpha
• Lovastatin
• rho GTP-Binding Proteins

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Movement
• Cells, Cultured
• E-Selectin (biosynthesis, genetics)
• Endothelium, Vascular (drug effects, metabolism)
• Humans
• Lovastatin (pharmacology, therapeutic use)
• Neoplasms (drug therapy, pathology)
• Signal Transduction
• Transcription, Genetic
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)
• rho GTP-Binding Proteins (antagonists & inhibitors)