Due to their altered metabolism
cancer cells are more sensitive to
proteasome inhibition or changes of
copper levels than normal cells. Thus, the development of
copper complexes endowed with
proteasome inhibition features has emerged as a promising anticancer strategy. However, limited information is available about the exact mechanism by which
copper inhibits
proteasome. Here we show that Cu(II)
ions simultaneously inhibit the three
peptidase activities of isolated 20S proteasomes with potencies (IC50) in the micromolar range. Cu(II)
ions, in cell-free conditions, neither catalyze red-ox reactions nor disrupt the assembly of the
20S proteasome but, rather, promote conformational changes associated to impaired channel gating. Notably, HeLa cells grown in a Cu(II)-supplemented medium exhibit decreased
proteasome activity. This effect, however, was attenuated in the presence of an
antioxidant. Our results suggest that if, on one hand, Cu(II)-inhibited 20S activities may be associated to conformational changes that favor the closed state of the core particle, on the other hand the complex effect induced by Cu(II)
ions in
cancer cells is the result of several concurring events including ROS-mediated
proteasome flooding, and disassembly of the
26S proteasome into its 20S and 19S components.