Abstract
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 (IC 50) 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.
| Original language | English |
|---|---|
| Pages (from-to) | 33444 |
| Journal | Scientific Reports |
| Volume | 6 |
| DOIs | |
| Publication status | Published - Sep 16 2016 |
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Copper(II) ions affect the gating dynamics of the 20S proteasome : A molecular and in cell study. / Santoro, Anna Maria; Monaco, Irene; Attanasio, Francesco; Lanza, Valeria; Pappalardo, Giuseppe; Tomasello, Marianna Flora; Cunsolo, Alessandra; Rizzarelli, Enrico; De Luigi, Ada; Salmona, Mario; Milardi, Danilo.
In: Scientific Reports, Vol. 6, 16.09.2016, p. 33444.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Copper(II) ions affect the gating dynamics of the 20S proteasome
T2 - A molecular and in cell study
AU - Santoro, Anna Maria
AU - Monaco, Irene
AU - Attanasio, Francesco
AU - Lanza, Valeria
AU - Pappalardo, Giuseppe
AU - Tomasello, Marianna Flora
AU - Cunsolo, Alessandra
AU - Rizzarelli, Enrico
AU - De Luigi, Ada
AU - Salmona, Mario
AU - Milardi, Danilo
PY - 2016/9/16
Y1 - 2016/9/16
N2 - 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 (IC 50) 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.
AB - 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 (IC 50) 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.
UR - http://www.scopus.com/inward/record.url?scp=84987935106&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84987935106&partnerID=8YFLogxK
U2 - 10.1038/srep33444
DO - 10.1038/srep33444
M3 - Article
VL - 6
SP - 33444
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
ER -