Ionizing radiation-induced E-selectin gene expression and tumor cell adhesion is inhibited by lovastatin and all-trans retinoic acid.

Abstract

E-selectin mediated tumor cell adhesion plays an important role in metastasis. Here we show that ionizing radiation (IR) induces E-selectin gene and protein expression in human endothelial cells at therapeutically relevant dose level. E-selectin expression is accompanied by an increase in the adhesion of human colon carcinoma cells to primary human umbilical vein endothelial cells (HUVEC). The HMG-CoA reductase inhibitor lovastatin impairs IR-stimulated E-selectin expression as analyzed at the level of the protein, mRNA and promoter. Inactivation of Rho GTPases either by use of Clostridium difficile toxin A or by co-expression of dominant-negative Rho blocked IR-induced E-selectin gene induction, indicating Rho GTPases to be essential. Radiation-induced expression of E-selectin was also blocked by all-trans retinoic acid (at-RA), whereas 9-cis retinoic acid was ineffective. Abrogation of IR-stimulated E-selectin expression by lovastatin and at-RA reduced tumor cell adhesion in a dose-dependent manner. Combined treatment with lovastatin and at-RA exerted additive inhibitory effects on radiation-induced E-selectin expression and tumor cell adhesion. Therefore, application of statins and at-RA might have clinical impact in protecting against E-selectin-promoted metastasis, which might arise as an unwanted side effect from radiation treatment.

• Authors: Tobias Nübel, Wolfgang Dippold, Bernd Kaina, Gerhard Fritz
• Journal: Carcinogenesis (Carcinogenesis) Vol. 25 Issue 8 Pg. 1335-44 (Aug 2004) ISSN: 0143-3334 [Print] England
• PMID: 14988223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• E-Selectin
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• NF-kappa B
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• Tretinoin
• Lovastatin
• rho GTP-Binding Proteins

Topics

• Blotting, Western
• Cell Adhesion
• Cell Line, Tumor
• Cells, Cultured
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Radiation
• E-Selectin (biosynthesis, metabolism)
• Endothelium, Vascular (cytology)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Intercellular Adhesion Molecule-1 (metabolism)
• Lovastatin (pharmacology)
• NF-kappa B (metabolism)
• Neoplasms (metabolism)
• Promoter Regions, Genetic
• RNA, Messenger (metabolism)
• Radiation, Ionizing
• Reverse Transcriptase Polymerase Chain Reaction
• Transcriptional Activation
• Tretinoin (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• rho GTP-Binding Proteins (metabolism)