Carcinogenesis Advance Access published online on February 26, 2004
Carcinogenesis, doi:10.1093/carcin/bgh133
© 2004 by Oxford University Press
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CANCER BIOLOGY
1 1University of Mainz, Institute of Toxicology, Division of Applied Toxicology, Obere Zahlbacher Str. 67, D-55131 Mainz
* Corresponding author. E-mail: fritz{at}mail.uni-mainz.de.
Received 13 November 2003
; revised 17 February 2004
; accepted 20 February 2004
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 (9c-RA) 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 unwished side effect from radiation treatment.
Ionizing radiation, E-selectin, tumor cell adhesion, Statins, Rho GTPases
Ionizing radiation-induced E-selectin gene expression and tumor cell adhesion is inhibited by lovastatin and all-trans retinoic acid
2 2St. Vincenz and Elisabeth Hospital, An der Goldgrube 11, D-55131 Mainz
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