Amlexanox reversibly inhibits cell migration and proliferation and induces the Src-dependent disassembly of actin stress fibers in vitro.
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.
Landriscina
M
M
Center for Molecular Medicine, Maine Medical Center Research Institute, South Portland, Maine 04106, USA.
Prudovsky
I
I
Mouta Carreira
C
C
Soldi
R
R
Tarantini
F
F
Maciag
T
T
D016475:3T3 Cells; D000199:Actins / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001011:Aorta; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D051356:Cortactin; D003599:Cytoskeleton / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000502:physiology; D016391:Genes, src; D006801:Humans; D007739:L Cells; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology; D013256:Steroids; D014162:Transfection; D014471:Umbilical Veins; D014982:Xenopus laevis
D000199:Actins; D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; C495868:CTTN protein, human; D051356:Cortactin; C495869:Cttn protein, mouse; C495870:Cttn protein, rat; D008840:Microfilament Proteins; D011956:Receptors, Cell Surface; D013256:Steroids; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; C045742:amlexanox