Carcinogenesis Advance Access originally published online on February 26, 2004
Carcinogenesis 2004 25(8):1335-1344; doi:10.1093/carcin/bgh133
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Carcinogenesis vol.25 no.8 © Oxford University Press 2004; all rights reserved.
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Ionizing radiation-induced E-selectin gene expression and tumor cell adhesion is inhibited by lovastatin and all-trans retinoic acid
1 University of Mainz, Institute of Toxicology, Division of Applied Toxicology, Obere Zahlbacher Str. 67, D-55131 Mainz and 2 St Vincenz and Elisabeth Hospital, An der Goldgrube 11, D-55131 Mainz, Germany
3 To whom correspondence should be addressed Email: fritz{at}mail.uni-mainz.de
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.
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