Tianeptine sodium salt suppresses TNF-alpha-induced expression of matrix metalloproteinase-9 in human carcinoma cells via suppression of the PI3K/Akt-mediated NF-kappa B pathway

Abstract

Tianeptine sodium salt (TSS) is a selective facilitator of serotonin, but there are no reports regarding anti-invasive effects of TSS. Therefore, we investigated the effect of TSS on the expression of matrix metalloproteinase-9 (MMP-9) and invasion in three different human carcinoma cell lines. Our findings showed that MMP-9 activity was significantly increased in response to tumor necrosis factor-alpha (TNF-alpha), and that TSS reduced TNF-alpha-induced MMP-9 activity in a dose-dependent manner. TSS also downregulated both MMP-9 expression and TNF-alpha-induced MMP-9 promoter activity. Using a matrigel invasion assay, we showed that TSS significantly attenuated invasive rates in TNF-alpha-stimulated LNCaP prostate carcinoma cells. Furthermore, TSS suppressed TNF-alpha-induced NF-kappa B activity, which is a potential transcriptional factor for regulating many invasive genes, including MMP-9, by suppressing I kappa B degradation and nuclear translocation of NF-kappa B subunits in LNCaP prostate carcinoma cells. TSS also downregulated TNF-alpha-induced phosphorylation of phosphatidyl-inositol 3 kinase (PI3K) and Akt, and a selective PI3K/Akt inhibitor, LY294002, diminished TNF-alpha-induced NF-kappa B activation followed by levels of MMP-9, suggesting that TSS also reduces MMP-9 expression by inhibiting the PI3K/Akt-mediated NF-kappa B pathway. These results indicate that TSS is a potential anti-invasive agent by suppression of TNF-alpha-induced MMP-9 expression via inhibition of PI3K/Akt-mediated NF-kappa B activity. (C) 2014 Elsevier B.V. All rights reserved.