Proteomics revealed the crosstalk between copper stress and cuproptosis, and explored the feasibility of curcumin as anticancer copper ionophore

As an essential micronutrient element in organisms, copper controls a host of fundamental cellular functions. Recently, copper-dependent cell growth and proliferation have been defined as "cuproplasia". Conversely, "cuproptosis" represents copper-dependent cell death, in a nonapoptotic manner. So far, a series of copper ionophores have been developed to kill cancer cells. However, the biological response mechanism of copper uptake has not been systematically analyzed. Based on quantitative proteomics, we revealed the crosstalk between copper stress and cuproptosis in cancer cells, and also explored the feasibility of curcumin as anticancer copper ionophore. Copper stress not only couples with cuproptosis, but also leads to reactive oxygen species (ROS) stress, oxidative damage and cell cycle arrest. In cancer cells, a feedback cytoprotection mechanism involving cuproptosis mediators was discovered. During copper treatment, the activation of glutamine transporters and the loss of Fe-S cluster proteins are the facilitators and results of cuproptosis, respectively. Through copper depletion, glutathione (GSH) blocks the cuproptosis process, rescues the activation of glutamine transporters, and prevents the loss of Fe-S cluster proteins, except for protecting cancer cells from apoptosis, protein degradation and oxidative damage. In addition, the copper ionophore curcumin can control the metabolisms of lipids, RNA, NADH and NADPH in colorectal cancer cells, and also up-regulates positive cuproptosis mediators. This work not only established the crosstalk between copper stress and cuproptosis, but also discolored the suppression and acceleration of cuproptosis by GSH and curcumin, respectively. Our results are significant for understanding cuproptosis process and developing novel anticancer reagents based on cuproptosis.