Abstract
We have previously reported that when mixed with copper, 8-hydroxyquinoline (8-OHQ) and its analog clioquinol (CQ) inhibited the proteasomal activity and proliferation in cultured human cancer cells. CQ treatment of high-copper-containing human tumor xenografts also caused cancer suppression, associated with proteasome inhibition in vivo. However, the nature of the copper dependence of these events has not been elucidated experimentally. In the current study, using chemical probe molecules that mimic the structures of 8-OHQ and CQ, but have no copper-binding capability, we dissected the complex cellular processes elicited by 8-OHQ–Cu and CQ–Cu mixtures and revealed that copper binding to 8-OHQ or CQ is required for transportation of the copper complex into human breast cancer cells and the consequent proteasome-inhibitory, growth-suppressive, and apoptosis-inducing activities. In contrast, the non-copper-binding analogs of 8-OHQ or CQ blocked the very first step—copper binding—in this chain of events mediated by 8-OHQ–Cu or CQ–Cu.
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Acknowledgments
This work was supported by Shandong University, the American Lebanese Syrian Associated Charities (ALSAC), and St. Jude Children’s Research Hospital (B.Y.)., and research funds from the Karmanos Cancer Institute of Wayne State University (Q.P.D.), the Department of Defense Breast Cancer Research Program (W81XWH-04-1-0688, DAMD17-03-1-0175; Q.P.D.) and the National Cancer Institute (1R01CA120009, 1R21CA139386-01; Q.P.D.).
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Zhai, S., Yang, L., Cui, Q.C. et al. Tumor cellular proteasome inhibition and growth suppression by 8-hydroxyquinoline and clioquinol requires their capabilities to bind copper and transport copper into cells. J Biol Inorg Chem 15, 259–269 (2010). https://doi.org/10.1007/s00775-009-0594-5
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DOI: https://doi.org/10.1007/s00775-009-0594-5