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Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

T. Nehybová, J. Šmarda, L. Daniel, M. Stiborek, V. Kanický, I. Spasojevič, J. Preisler, J. Damborský, P. Beneš,

. 2017 ; 18 (4) : . [pub] 20170329

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc17023169

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.

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$a Nehybová, Tereza $u Laboratory of Cell Differentiation, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. 322903@mail.muni.cz. International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne's University Hospital, Pekarska 53, 656 91 Brno, Czech Republic. 322903@mail.muni.cz.
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$a 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.
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$a Šmarda, Jan $u Laboratory of Cell Differentiation, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. smarda@sci.muni.cz.
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$a Daniel, Lukáš $u International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne's University Hospital, Pekarska 53, 656 91 Brno, Czech Republic. 211165@mail.muni.cz. Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. 211165@mail.muni.cz.
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$a Stiborek, Marek $u Department of Chemistry, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. 408516@mail.muni.cz.
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$a Kanický, Viktor $u Department of Chemistry, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. viktor.kanicky@ceitec.muni.cz. CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. viktor.kanicky@ceitec.muni.cz.
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$a Spasojevič, Ivan $u Department of Life Sciences, Institute for Multidisciplinary Research, University of Belgrade, 11030 Belgrade, Serbia. redoxsci@gmail.com.
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$a Preisler, Jan $u Department of Chemistry, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. preisler@chemi.muni.cz. CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. preisler@chemi.muni.cz.
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$a Damborský, Jiří $u International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne's University Hospital, Pekarska 53, 656 91 Brno, Czech Republic. jiridamborsky0@gmail.com. Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. jiridamborsky0@gmail.com.
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$a Beneš, Petr $u Laboratory of Cell Differentiation, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. pbenes@sci.muni.cz. International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne's University Hospital, Pekarska 53, 656 91 Brno, Czech Republic. pbenes@sci.muni.cz.
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