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Lovastatin inhibits Rho‐regulated expression of E‐selectin by TNF‐α and attenuates tumor cell adhesion
Author(s) -
Nübel Tobias,
Dippold Wolfgang,
Kleinert Hartmut,
Kaina Bernd,
Fritz Gerhard
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0261fje
Subject(s) - lovastatin , rhob , tumor necrosis factor alpha , rhoa , e selectin , microbiology and biotechnology , biology , cell adhesion , chemistry , cancer research , signal transduction , cell , biochemistry , immunology , cholesterol
E‐selectin mediated cell‐cell adhesion plays an important role in inflammatory processes and extravasation of tumor cells. Tumor necrosis factor‐α (TNF‐α) 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‐α 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 (IC 50 <0.1 µM). Lovastatin‐mediated block of TNF‐α 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‐α 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‐α stimulated adhesion of colon carcinoma cells to HUVEC. Furthermore, low concentration of lovastatin (i.e., ≤1 µM) attenuated TNF‐α induced tumor cell invasion in vitro. The data support the view that statins might be clinically useful in protection against E‐selectin mediated metastasis.