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

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RESEARCH PRODUCT

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

Gerhard Fritz Wolfgang Dippold Bernd Kaina Tobias Nübel

subject

Transcriptional Activation rho GTP-Binding Proteins Cancer Research Blotting Western Intercellular Adhesion Molecule-1 Retinoic acid Enzyme-Linked Immunosorbent Assay Tretinoin chemistry.chemical_compound Genes Reporter Tretinoin Cell Line Tumor Neoplasms Radiation Ionizing E-selectin Gene expression Cell Adhesion medicine Humans Lovastatin RNA Messenger Promoter Regions Genetic Cell adhesion Cells Cultured Dose-Response Relationship Drug biology Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Cell adhesion molecule NF-kappa B Dose-Response Relationship Radiation General Medicine Intercellular Adhesion Molecule-1 Gene Expression Regulation Neoplastic chemistry biology.protein Cancer research Endothelium Vascular Lovastatin Hydroxymethylglutaryl-CoA Reductase Inhibitors E-Selectin medicine.drug

description

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.

year	journal	country	edition	language
2004-03-11	Carcinogenesis

https://doi.org/10.1093/carcin/bgh133