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Tumor Biology |
Lineberger Comprehensive Cancer Center [S. M., J. S. P.] and Departments of Medicine [J. S. P.] and Microbiology and Immunology [J. S. P.], University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, and Department of Otolaryngology, School of Medicine [S. M., T. Y., H. T., M. F.], and Department of Molecular Virology and Oncology, Cancer Research Institute [H. S.], Kanazawa University, Ishikawa 920-8640, Japan
Matrix metalloproteinases (MMPs) are thought to play crucial roles in
tumor invasion and metastasis. Because we have shown that EBV latent
membrane protein 1 (LMP1) enhances MMP-9 expression by activation of
nuclear factor (NF)-
B and activator protein (AP)-1 (T. Yoshizaki,
et al., Proc. Natl. Acad. Sci. USA, 95:
3621–3626, 1998), we therefore tested whether up-regulation of MMP-9
by LMP1 could be correlated with enhanced invasiveness of tumor cells
in vitro. Whether aspirin and sodium salicylate could
reduce invasiveness and whether LMP1 could enhance MMP-9 expression in
tumors grown in nude mice were also tested. C33A cells stably
expressing LMP1 had increased expression of MMP-9 and showed greater
invasion through reconstituted basement membrane compared with
vector-transfected C33A cells (P < 0.02). Treatment with aspirin or sodium salicylate inhibited
invasiveness of the LMP1-expressing C33A cells
(P < 0.03) and suppressed both the
LMP1-induced MMP-9 expression in zymographic analyses and LMP1-induced
MMP-9 promoter activity in CAT reporter assays
(P < 0.01). Endogenous MMP-2 levels were
unaffected by either drug. Both drugs repressed the CAT activity of the
truncated MMP-9 promoter construct, which only contained a binding site
for AP-1, to the basal level (P < 0.05).
Moreover, EMSA indicated that the effects of the salicylates were
through the inhibition of not only NF-B but also AP-1 binding
activity. Inhibitory effect of salicylates could be reversed by p50/p65
subunits of NF-B or c-Jun overexpression. The inhibitory effect of
aspirin on NF-B activity was attributable to the inhibition of IB
kinase activity. Finally, tumors derived from C33A cells stably
expressing LMP1 grown in nude mice showed enhanced MMP-9 levels
compared with tumors derived from vector-transfected C33A cells. This
enhancement was inhibited by treatment of the mice with aspirin. These
results suggest that aspirin may be able to suppress invasion and
metastasis of EBV-associated tumors that express LMP1 by suppression of
MMP-9.
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