Gold compounds inhibit adhesion of human cancer cells to vascular endothelial cells

Abstract

Transcription factor NF-κB controls the expression of a number of genes including those for cell adhesion molecules such as E-selectin, ICAM-1 and VCAM-1. These cell adhesion molecules are known to play important roles in a critical step of tumor metastasis; the arrest of tumor cells on the venous or capillary bed of the target organ. NF-κB is activated by extracellular signals such as those elicited by the proinflammatory cytokines, TNF and IL-1. Here we demonstrate that IL-1β induces nuclear translocation of NF-κB in human umbilical vein endothelial cells (HUVEC) followed by induction of cell surface expression of E-selectin, ICAM-1 and VCAM-1, and subsequently augments adhesion of cancer cells expressing sialyl Lewis antigen, a ligand of E-selectin. We also demonstrated that the adhesion of tumor cells to IL-1β-treated HUVEC was inhibited by gold compounds such as aurothioglucose and aurothiomalate. These observations indicate the involvement of NF-κB in cancer metastasis and suggest the feasibility of using gold compounds to prevent metastasis.

Introduction

Although gold compounds have been used to treat rheumatoid arthritis (RA), the mechanism of action of gold compounds in this respect has not been clarified. Yang et al. recently demonstrated that gold compounds inhibited DNA binding of NF-κB in vitro [1]. Yoshida et al. and Traber et al. demonstrated their effects in NF-κB-dependent gene expression in cultured cells [2], [3].

NF-κB is a pleiotropic transcription factor complex that controls the expression of a wide variety of genes, including genes for cytokines such as IL-1, IL-6, IL-8, IFN-α, and TNF-α, as well as genes for some cell adhesion molecules (CAMs) including E-selectin, ICAM-1, VCAM-1 and viral genes including HIV-1 [4], [5]. The active NF-κB complex is composed of two subunits designated p50 and p65 (RelA) [6], [7]. In resting cells, NF-κB exists as an inactive form in the cytoplasm associated with the inhibitory molecule IκB [4], [5], [6], [7]. Upon stimulation by extracellular signals such as the proinflammatory cytokines TNF-α and IL-1β, IκB is degradated and NF-κB moves into the nucleus to activate target genes. It was found that the DNA-binding activity of NF-κB is regulated by an oxido-reductive mechanism (redox regulation) [8]. Furthermore, expression of NF-κB has been found to promote cell survival, inhibiting the induction of apoptosis [9].

In this study, we demonstrated that adhesion of human cancer cells to HUVEC was augmented through activation of NF-κB by IL-1β, and that gold compounds could block this process by inhibiting the induction of relevant CAMs.