Molecular study on copper-mediated tumor proteasome inhibition and cell death.
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.
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.|Key Laboratory of Marine Chemistry Engineering and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China.|Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao 266101, P.R. China.
Yan
Y
Xiao
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
D I
DI
Chen
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.|Key Laboratory of Marine Chemistry Engineering and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China.
Xia
X
Zhang
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Qiuzhi
Q
Cui
Key Laboratory of Marine Chemistry Engineering and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China.
Yuhua
Y
Fan
Key Laboratory of Marine Chemistry Engineering and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China.
Caifeng
C
Bi
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Q Ping
QP
Dou
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010618:Phenanthrolines / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D002614:Chelating Agents; D010618:Phenanthrolines; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D003300:Copper; C002701:neocuproine; C028419:cuprous chloride; D046988:Proteasome Endopeptidase Complex; C029892:cupric chloride