In melanoma, transition to the vertical growth phase is the critical step in 
conversion to a deadly malignant disease. Here, we offer the first evidence that 
an antioxidant enzyme has a key role in this transition. We found that the 
antioxidant enzyme peroxiredoxin-2 (Prx2) inversely correlated with the 
metastatic capacity of human melanoma cells. Silencing Prx2 expression 
stimulated proliferation and migration, whereas ectopic expression of Prx2 
produced the opposite effect. Mechanistic investigations indicated that Prx2 
negatively regulated Src/ERK activation status, which in turn fortified adherens 
junctions function by increasing E-cadherin expression and 
phospho-Y654-dependent retention of β-catenin in the plasma membrane. In murine 
melanoma cells, Prx2 silencing enhanced lung metastasis in vivo. Interestingly, 
the natural compound gliotoxin, which is known to exert a Prx-like activity, 
inhibited proliferation and migration as well as lung metastasis of 
Prx2-deficient melanoma cells. Overall, our findings reveal that Prx2 is a key 
regulator of invasion and metastasis in melanoma, and also suggest a 
pharmacologic strategy to effectively decrease deadly malignant forms of this 
disease.