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Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

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NEHYBOVÁ Tereza ŠMARDA Jan DANIEL Lukáš STIBOREK Marek KANICKÝ Viktor SPASOJEVIČ Ivan PREISLER Jan DAMBORSKÝ Jiří BENEŠ Petr

Rok publikování 2017
Druh Článek v odborném periodiku
Časopis / Zdroj International Journal of Molecular Sciences
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www http://www.mdpi.com/1422-0067/18/4/729
Doi http://dx.doi.org/10.3390/ijms18040729
Obor Genetika a molekulární biologie
Klíčová slova breast cancer; copper; proteasome; reactive oxygen species; wedelolactone
Popis 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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