The
metal ion
copper is a cofactor essential for maintaining normal
biological and physical functions in human beings. High
copper levels have been found in variety of
tumor tissues and are involved in
tumor angiogenesis processes. The
ubiquitin-
proteasome system plays an important role in cell growth and apoptosis and has been shown as a novel target for
cancer therapy. We previously reported that some organic
copper complexes can inhibit the proteasomal
chymotrypsin-like activity and induce apoptosis in human
cancer cells and xenograft models. In the current study, we investigated the effect of oxidation status of
copper, Cu(I) or Cu(II), on inhibition of
proteasome activity, induction of apoptosis, and induction of
reactive oxygen species (ROS) in human
cancer cells. We report four major findings here: i) both Cu(I) and Cu(II) could inhibit the
chymotrypsin-like activity of purified
20S proteasome, but Cu(I) was more potent than Cu(II), ii) purified
20S proteasome protein was able to reduce Cu(II) to Cu(I), suggesting that Cu(I) is the oxidation status of
copper that directly reacts with the
proteasome, iii) when complexed with the
copper ligand neocuproine, Cu(I) showed higher ability to induce ROS production in
cancer cells, compared with Cu(II), iv) addition of a ROS scavenger in the
cancer cell culture-blocked
copper-induced ROS generation, but did not overcome
copper-mediated
proteasome-inhibitory and cell death-inducing events, demonstrating the ROS-independent
proteasome-inhibitory property of
copper complexes.