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J. Biol. Chem., Vol. 275, Issue 42, 32753-32762, October 20, 2000
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From the Center for Molecular Medicine, Maine Medical Center
Research Institute, South Portland, Maine 04106
Amlexanox binds S100A13 and inhibits
the release of fibroblast growth factor 1 (FGF1). Because members of
the S100 gene family are known to be involved with the function of the
cytoskeleton, we examined the ability of amlexanox to modify the
cytoskeleton and report that amlexanox induces a dramatic reduction in
the presence of actin stress fibers and the appearance of a random, non-oriented distribution of focal adhesion sites. Correspondingly, amlexanox induces the complete and reversible non-apoptotic inhibition of cell migration and proliferation, and although amlexanox does not
induce either the down-regulation of F-actin levels or the depolymerization of actin filaments, it does induce the tyrosine phosphorylation of cortactin, a Src substrate known to regulate actin
bundling. In addition, a dominant negative form of Src is able to
partially rescue cells from the effect of amlexanox on both the actin
cytoskeleton and cell migration. In contrast, the inhibition of cell
proliferation by amlexanox correlates with the inhibition of cyclin D1
expression without interference of the receptor tyrosine
kinase/mitogen-activated protein kinase signaling pathway. Last, the
ability of amlexanox to inhibit FGF1 release is reversible and
correlates with the restoration of the actin cytoskeleton, suggesting a
role for the actin cytoskeleton in the FGF1 release pathway.
Amlexanox Reversibly Inhibits Cell Migration and
Proliferation and Induces the Src-dependent Disassembly
of Actin Stress Fibers in Vitro*
,
*
This work was supported in part by National Institutes of
Health Grants HL35627, HL32348, and AG07450 (to T. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a fellowship from the Catholic University of Rome.
§
Present address: Massachusetts General Hospital, Harvard Medical
School, 100 Blossom St., Boston, MA 02114.
¶
Present address: Dept. of Geriatric Medicine, University of
Florence, School of Medicine, Florence, Italy.
To whom correspondence should be addressed: Center for
Molecular Medicine, Maine Medical Center Research Institute, 125 John Roberts Rd., South Portland, Maine 04106. Tel.: 207-761-9783; Fax:
207-828-8071; E-mail: maciat@mail.mmc.org.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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