Journal Article

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

Tobias Nübel, Wolfgang Dippold, Bernd Kaina and Gerhard Fritz

in Carcinogenesis

Volume 25, issue 8, pages 1335-1344
Published in print August 2004 | ISSN: 0143-3334
Published online August 2004 | e-ISSN: 1460-2180 | DOI:
Ionizing radiation-induced E-selectin gene expression and tumor cell adhesion is inhibited by lovastatin and all-trans retinoic acid

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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.

Keywords: at-RA, all-trans retinoic acid; HUVEC, human umbilical vein endothelial cells; IR, ionizing radiation; 9c-RA, 9-cis retinoic acid; ToxA, Clostridium difficile toxin A

Journal Article.  7616 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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