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Int. J. Mol. Sci. 2017, 18(4), 729; doi:10.3390/ijms18040729

Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

Laboratory of Cell Differentiation, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne’s University Hospital, Pekarska 53, 656 91 Brno, Czech Republic
Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
Department of Chemistry, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
Department of Life Sciences, Institute for Multidisciplinary Research, University of Belgrade, 11030 Belgrade, Serbia
Author to whom correspondence should be addressed.
Academic Editor: Toshio Morikawa
Received: 1 February 2017 / Revised: 20 March 2017 / Accepted: 25 March 2017 / Published: 29 March 2017
(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)
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Wedelolactone is a multi-target natural plant coumestan exhibiting cytotoxicity towards cancer cells. Although several molecular targets of wedelolactone have been recognized, the molecular mechanism of its cytotoxicity has not yet been elucidated. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like, and caspase-like activities of proteasome in breast cancer cells. The proteasome inhibitory effect of wedelolactone was documented by (i) reduced cleavage of fluorogenic proteasome substrates; (ii) accumulation of polyubiquitinated proteins and proteins with rapid turnover in tumor cells; and (iii) molecular docking of wedelolactone into the active sites of proteasome catalytic subunits. Inhibition of proteasome by wedelolactone was independent on its ability to induce reactive oxygen species production by redox cycling with copper ions, suggesting that wedelolactone acts as copper-independent proteasome inhibitor. We conclude that the cytotoxicity of wedelolactone to breast cancer cells is partially mediated by targeting proteasomal protein degradation pathway. Understanding the structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells. View Full-Text
Keywords: breast cancer; copper; proteasome; reactive oxygen species; wedelolactone breast cancer; copper; proteasome; reactive oxygen species; wedelolactone

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Nehybová, T.; Šmarda, J.; Daniel, L.; Stiborek, M.; Kanický, V.; Spasojevič, I.; Preisler, J.; Damborský, J.; Beneš, P. Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells. Int. J. Mol. Sci. 2017, 18, 729.

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