Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

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.

The Multiple Roles of Glucose-6-Phosphate Dehydrogenase in Tumorigenesis and Cancer Chemoresistance

“…Wedelolactone, a small molecular compound isolated from Ecliptaalba and Wedelia calendulacea has attracted much attention because of its extensive pharmacological activi-ties, including hepatoprotective, anti-oxidation, anti-inflammatory, immunomodulatory and anti-fibrotic effects, etc. [87,[110][111][112] Recent researches has shown that Wedelolactone exhibited a potent anticancer activity against different solid tumors, such as breast, colon and prostate cancers, through inhibiting multiple kinases, the androgen receptor, 5-lipoxygenase and the c-Myc protein [87]. Lately, Luo et al identified Wedelolactone as a G6PD inhibitor by the high-throughput screening assay.…”

Environmental pollutant N‐N′ethylnitrosourea‐induced leukemic NLRP3 inflammasome activation and its amelioration by Eclipta prostrata and its active compound wedelolactone

“…One such ethnomedicinal herb Eclipta prostrata (EP) also known as Bhringaraj in Ayurveda, is established for its anti‐inflammatory and anticancer properties 19–24 . Wedelolactone (WDL), the major coumestan derivative of this herb, is exclusively reported for anticancer effects and has been investigated to hinder the overexpression of NLRP3 inflammasome 25–34 …”

The Potential Role of Wedololactone in Treating Particle-induced Osteolysis _A Mouse Calvarial Model

“…WDL is considered a traditional Chinese herbal medicine with strong anti-in ammatory properties [24][25][26][27][28]. Recent studies have shown that WDL can help promote hair growth [29] and is hepatoprotective [30,31], neuroprotective [32] and anti-carcinogenic [33,34].…”