Tissue inhibitor of metalloproteinase-1 decreased chemosensitivity of MDA-435 breast cancer cells to chemotherapeutic drugs through the PI3K/AKT/NF-κB pathway

TIMP-1 is well known to be capable of inhibiting apoptosis. Elevated levels of TIMP-1 in tumor tissue have been shown to be strongly associated with a poor response to chemotherapy. In this study, using conventional cytotoxic drugs commonly used in the treatment of breast cancer, we investigated how TIMP-1 influenced the efficacy using breast cell lines. Our data demonstrated that overexpression of TIMP-1 could significantly decrease the sensitivity of MDA-435 breast cancer cells to epirubicin and paclitaxel. TIMP-1 can potently activate phosphatidylinositol 3-kinase (PI3 K)/Akt and nuclear factor-kappaB (NF-kappa B) signaling. Furthermore, the TIMP-1-induced attenuation of the effect of epirubicin and paclitaxel was reversed by the PI3K/Akt chemical inhibitor LY294002 and the NF-kappa B inhibitor pyrrolidine dithiocarbamate (PDTC), showing that the PI3 K/Akt and NF-kappa B signaling pathway was involved in the TIMP-1-induced effect on chemoresistance. Taken together, our results indicate that TIMP-1 decreased chemosensitivity through the PI3 K/Akt/NF-kappa B signal transduction pathway in MDA-435 breast cancer cells. (C) 2011 Elsevier Masson SAS. All rights reserved.