Peroxiredoxin 6 triggers melanoma cell growth by increasing arachidonic acid-dependent lipid signalling

Tumour cells are reported to display an imbalance in the levels of ROS (reactive oxygen species). Frequently, elevated ROS production goes along with compensatory up-regulation of antioxidant enzymes. Accordingly, we found in a previous study that protein levels of several peroxiredoxins, including PRDX6 (peroxiredoxin 6), are highly elevated in experimentally induced melanomas. In the present study, we investigated the functional role of PRDX6 in human melanoma cells. PRDX6 is a bifunctional enzyme, which harbours iPLA₂ (Ca²⁺-independent phospholipase A₂) activity in addition to its peroxidase function. Our results show that PRDX6 is strongly expressed in most melanoma cells and its expression levels are maintained in a post-transcriptional manner, particularly by EGFR (epidermal growth factor receptor)-dependent signalling. PRDX6 enhances cell viability mainly by enhancing proliferation, which goes along with activation of Src family kinases. Interestingly, we were able to show that the phospholipase activity of the enzyme mediates the pro-proliferative effect of PRDX6. We identified AA (arachidonic acid) as a crucial effector of PRDX6-dependent proliferation and inducer of Src family kinase activation. These results support further the biological importance of the emerging field of lipid signalling in melanoma and highlight the particular functional relevance of PRDX6-dependent phospholipase activity.