A Novel Anticancer Effect of Thalidomide: Inhibition of Intercellular Adhesion Molecule-1-Mediated Cell Invasion and Metastasis through Suppression of Nuclear Factor-Kappa B
Resource
CLINICAL CANCER RESEARCH v.12 n.23 pp.7165-7173
Journal
CLINICAL CANCER RESEARCH
Journal Volume
v.12
Journal Issue
n.23
Pages
7165-7173
Date Issued
2006
Date
2006
Author(s)
LIN, YI-CHUN
SHUN, CHIA-TUNG
WU, MING-SHIANG
CHEN, CHING-CHOW
Abstract
Purpose: Thalidomide has been reported to have antiangiogenic and antimetastatic effects. Intercellular adhesion molecule-1 (ICAM-1) was shown to be involved in monocyte adherence to epithelial cells and cancer cell invasion. In this study, we further investigated the role of ICAM-1 in tumorigenesis, including tumor formation and metastasis. ICAM-1 as a molecular target for cancer and the anticancer effect of thalidomide were investigated. Experimental Design: Expression of ICAM-1 protein in human lung cancer specimens was assessed by immunohistochemistry. ICAM-1 overexpressing A549 cells (A549/ICAM-1) were established to investigate the direct effect of ICAM-1 on in vitro cell invasion and in vivo tumor metastasis. Transient transfection and luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation were done to assess the activity and binding of nuclear factor-kappa B to the ICAM-1 promoter. A xenograft model in nude mice was conducted to evaluate the anticancer effect of thalidomide. Results: High expression of ICAM-1 in human lung cancer specimens was correlated with a greater risk of advanced cancers (stages III and IV). A549/ICAM-1 cells were shown to induce in vitro cell invasion and in vivo tumor metastasis. Anti-ICAM-1 antibody and thalidomide had inhibitory effect on these events. Thalidomide also suppressed tumor necrosis factor-alpha-induced ICAM-1 expression through inhibition of nuclear factor-kappa B binding to the ICAM-1 promoter. The in vivo xenograft model showed the effectiveness of thalidomide on tumor formation. Conclusion: These studies provide a framework for targeting ICAM-1 as a biologically based therapy for cancer, and thalidomide might be effective in human lung cancer.
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