MMP3 brings about epithelial–mesenchymal transition (EMT), which increases cellular motility and invasiveness, a key trait of tumour cells. The process requires changes in the actin cytoskeleton and, although the activities of RhoA and Cdc42 were unaffected by MMP3, the authors found that a previously identified splice variant of Rac1 — Rac1b — was upregulated and, indeed, was necessary for MMP-induced motility.
Could Rac1b mediate the pleiotropic effects that are caused by MMP3 and, if so, how? Previous studies have shown that active Rac can stimulate the production and release of mitochondrial superoxide into the cytoplasm, which can damage cells, potentiate tumour progression and be further converted into other destructive reactive oxygen species (ROS). Treating cells with MMP3 or expressing Rac1b increased cellular ROS levels, and this increase was inhibited by expressing dominant-negative Rac1. Transfecting cells with superoxide dismutase-2 (SOD2), a mitochondrial enzyme that reduces superoxide levels, inhibited MMP3-induced cell scattering, which indicates that MMP3- or Rac1b-induced mitochondrial superoxide production is required for EMT. Similarly, N-acetyl cysteine (NAC), a ROS quencher, inhibited the MMP3-induced downregulation of an epithelial marker and the upregulation of a mesenchymal marker and, consequently, blocked motility and invasion. Radisky et al. saw that MMP3-induced ROS also caused cellular DNA damage and genomic instability, which, again, could be induced independently by the ROS hydrogen peroxide and inhibited by NAC.
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