Regulation of MMP-2 and MMP-9 activities in response to treatment of α-lipoic acid

Abstract

Metastasis is main cause of death in cancer patient. Active matrix metalloproteinases (MMPs) play critical role in tumor invasion and metastasis. Many studies have shown that reactive oxygen species (ROS) increase the expression level and activation of MMPs through mitogen-activating protein kinase (MAPK) signaling pathway. a-Lipoic acid (LA), a disulfide compound produced in small quantity in cells, is a multifunctional antioxidant which may be useful in treating pathologies associated with redox imbalance. Based on those reports it was hypothesized that LA can inhibit MMPs expression through MAP Kinase pathway. The invasion of HT1080 human fibrosarcoma cells was inhibited by LA. Furthermore, Gelatin Zymography results displayed that MMP-2 and MMP-9 protein were decreased by LA in a concertaion dependent manner. LA reduced intracellular ROS even in the presence of PMA, a superoxide generator which also activate MMPs. As the oxidation of cystein residue by ROS has now been extended to the inhibition of several phosphatases important for MAPK activation, antioxidant role of LA could related to MMPs expression through the MAPK pathway. As LA concentration was increased, ERK protein level has not changed, but phosphorylation of ERK was reduced. To link MAPK and proteases expressions, the effects of LA of to transcription factors were examined. While cytosolic NF-K.13 was not affected by LA, nuclear translocation of NF-K13 was inhibited with the increased concentration of LA. The expression of c-Jun and c-Fos which are the components of AP-1, were not changed by LA. In this study, it was demonstrated that LA inhibited several essential steps of metastasis. LA has inhibitory effect on tumor cell invasion through MMP-2 and MMP-9 expression and this regulation is mediated by regulation of transcription factor such as NF-iB.