Arsenic trioxide (As2O3) inhibits invasion of HT1080 human fibrosarcoma cells: Role of nuclear factor‐κB and reactive oxygen species

Abstract

In order to define the role of As₂O₃ in regulating the tumor cell invasiveness, the effects of As₂O₃ on secretion of matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA), and in vitro invasion of HT1080 human fibrosarcoma cells were examined. As₂O₃ inhibited cell adhesion to the collagen matrix in a concentration dependent manner, whereas the same treatment enhanced cell to cell interaction. In addition, As₂O₃ inhibited migration and invasion of HT1080 cells stimulated with phorbol 12‐myristate 13‐aceate (PMA), and suppressed the expression of MMP‐2, ‐9, membrane type‐1 MMP, uPA, and uPA receptor (uPAR). In contrast, As₂O₃ increased the expression of tissue inhibitor of metalloproteinase (TIMP)‐1 and PA inhibitor (PAI)‐1, and reduced the MMP‐2, ‐9, and uPA promoter activity in the presence and absence of PMA. Furthermore, the promoter stimulating and DNA binding activity of nuclear factor‐κB (NF‐κB) was blocked by As₂O₃, whereas the activator protein‐1 activity was unchanged. Pretreatment of the cells with N‐acetyl‐L‐cysteine (NAC) significantly prevented suppression of MMPs and uPA secretion, DNA binding activity of NF‐κB, and in vitro invasion of HT1080 cells by As₂O₃, suggesting a role of reactive oxygen species (ROS) in this process. These results suggest that As₂O₃ inhibits tumor cell invasion by modulating the MMPs/TIMPs and uPA/uPAR/PAI systems of extracellular matrix (ECM) degradation. In addition, the generation of ROS and subsequent suppression of NF‐κB activity by As₂O₃ might partly be responsible for the phenomena. Overall, As₂O₃ shows potent activity controlling tumor cell invasiveness in vitro.