Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells
Nehybova T., Smarda, J., Daniel, L., Stiborek, M., Kanicky, V., Spasojevic, I., Preisler, J., Damborsky, J., Benes, P
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 18: E729 (2017)
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 been elucidated yet. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like and caspase-like activities of proteasome in the 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 a
structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells.