Copper chelator suppresses melanoma via inhibiting cuproplasia

Copper is essential for regulating the activity of critical proteins associated with tumor survival and metastasis. Elevated copper level can lead to cuproplasia, promoting the proliferation and growth of cancers. A copper chelator (CC) capable of inhibiting cuproplasia was designed to suppress the Cu-sensitive melanoma cells. CC sequestered cellular Cu ions through chelation, facilitated the generation of reactive oxygen/nitrogen species, induced endoplasmic reticulum and mitochondrion stresses, thus leading to paraptosis of melanoma cells in vitro and in vivo. Moreover, the redox imbalance and mitochondrial dysfunction caused by Cu depletion stimulated the mitogen-activated protein kinase (MAPK) pathway, further boosting the antimelanoma activity. In the tumor microenvironment, CC downregulated the expression of matrix metalloproteinases due to the chelation of Cu ions, thereby inhibiting the invasion and metastasis of melanoma cells. Collectively, CC is an effective inhibitor of cuproplasia that exerts comprehensive influence on diverse molecular pathways. Targeting cuproplasia constitutes a promising therapeutic approach for the Cu-sensitive melanoma.