In conclusion, in the present study we show that in melanoma cells high levels of virtually active Calpain-3 (variant hMp84) stimulate a variety of mechanisms which are eventually detrimental for cells, including p53 accumulation, modulation of several oxidative stress-related genes, increased formation of ROS (Reactive Oxygen Species) leading to oxidative modification of phospholipids, and DNA damage. Here, CAPN3 is linked to melanoma.