Abstract
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.
Highlights
The ubiquitin-proteasome system (UPS) controls a highly complex and tightly regulated process of cellular protein degradation
This study shows that wedelolactone acts as inhibitor of 20S/26S proteasome chymotrypsin-like and to lesser extent trypsin-like and caspase-like activities
Molecular docking revealed a productive binding of wedelolactone to the active sites of β1, β2, and β5 proteasomal subunits with a stronger preference for β5 subunit
Summary
The ubiquitin-proteasome system (UPS) controls a highly complex and tightly regulated process of cellular protein degradation. Due to increased rate of genomic mutations, transformed cells accumulate large quantities of misfolded or overexpressed proteins In response to such accumulation, malignant cells enhance the expression and activity of UPS [5,7]. It was found recently that wedelolactone inhibits topoisomerase IIα activity and blocks DNA synthesis in the breast cancer cells, and that these effects are promoted by copper ions, at least partially via redox interactions [12,22]. This study shows that wedelolactone acts as inhibitor of 20S/26S proteasome chymotrypsin-like and to lesser extent trypsin-like and caspase-like activities. Treatment of breast cancer cells with wedelolactone resulted in accumulation of ubiquitinated proteins and proteins representing typical proteasomal targets, such as p21, p27, p53, and Bax. Molecular docking revealed a productive binding of wedelolactone to the active sites of β1, β2, and β5 proteasomal subunits with a stronger preference for β5 subunit. This study concludes that wedelolactone acts as copper-independent inhibitor of proteasome
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