PMID- 14630701
OWN - NLM
STAT- MEDLINE
DCOM- 20040209
LR  - 20131121
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 18
IP  - 1
DP  - 2004 Jan
TI  - Lovastatin inhibits Rho-regulated expression of E-selectin by TNFalpha and 
      attenuates tumor cell adhesion.
PG  - 140-2
AB  - 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.
FAU - Nubel, Tobias
AU  - Nubel T
AD  - University of Mainz, Institute of Toxicology, Division of Applied Toxicology, 
      Mainz, Germany.
FAU - Dippold, Wolfgang
AU  - Dippold W
FAU - Kleinert, Hartmut
AU  - Kleinert H
FAU - Kaina, Bernd
AU  - Kaina B
FAU - Fritz, Gerhard
AU  - Fritz G
LA  - eng
PT  - Journal Article
DEP - 20031120
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Antineoplastic Agents)
RN  - 0 (E-Selectin)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 9LHU78OQFD (Lovastatin)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Cell Adhesion/drug effects
MH  - Cell Line, Tumor
MH  - Cell Movement
MH  - Cells, Cultured
MH  - E-Selectin/*biosynthesis/genetics
MH  - Endothelium, Vascular/drug effects/metabolism
MH  - Humans
MH  - Lovastatin/*pharmacology/therapeutic use
MH  - Neoplasms/*drug therapy/pathology
MH  - Signal Transduction
MH  - Transcription, Genetic
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors
MH  - rho GTP-Binding Proteins/*antagonists & inhibitors
EDAT- 2003/11/25 05:00
MHDA- 2004/02/11 05:00
CRDT- 2003/11/25 05:00
PHST- 2003/11/25 05:00 [pubmed]
PHST- 2004/02/11 05:00 [medline]
PHST- 2003/11/25 05:00 [entrez]
AID - 03-0261fje [pii]
AID - 10.1096/fj.03-0261fje [doi]
PST - ppublish
SO  - FASEB J. 2004 Jan;18(1):140-2. doi: 10.1096/fj.03-0261fje. Epub 2003 Nov 20.