Rhein suppresses matrix metalloproteinase production by regulating the Rac1/ROS/MAPK/AP-1 pathway in human ovarian carcinoma cells

Matrix metalloproteinases (MMPs) are a family of calcium-dependent zinc-containing endopeptidases, which play an integral role in migration and invasion of ovarian cancer. Racl proteins might mostly influence cell migration and invasion by generating endogenous reactive oxygen species. Therefore, inhibiting MMPs and regulating the Racl/ ROS/MAPK/AP-1 pathway may be a new therapeutic strategy for ovarian cancer. In this study, we found that rhein could suppress the invasion and migration of SKOV3-PM4 cells with characteristics of directional highly lymphatic metastasis. Phorbol 12-myristate 13-acetate (PMA), which is a Racl activator, significantly enhanced the expression levels of MMP-2, -3,-9 and-19 proteins, whereas the results of rhein and Racl inhibitor NSC23766 were just the opposite. The inhibitory effects of rhein were associated with the upregulation of tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2 and NM23H1. Subsequent mechanism studies revealed that rhein reduce the production of reactive oxygen species (ROS) and lower NADPH oxidase activity. Furthermore, rhein significantly inhibited JNK, AP-1 phosphorylation in the cells treated with PMA. The results obtained from the cells treated with NSC23766 alone or NSC23766 combined with rhein, were consistent with rhein treatment alone. Taken together, these results indicate that rhein may be a potential inhibitor of Racl and can inhibit the migration and invasion of SKOV3-PM4 cells through modulating matrix metalloproteinases and RAC1/ROS/MAPK/AP-1 signaling pathway-associated proteins.