Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor, and the main cause of treatment failure is malignant proliferation. Aberrations in Wnt/β-catenin signaling are associated with HCC development. Despite the improvements in overall survival made over the past decade from the advent of molecularly targeted therapies, these treatments do not have efficacy in all patients with different pathogeneses. Therefore, there is a demand for novel chemotherapeutic agents for HCC. To this end, we built a natural compound library and screened out a rotenoid named dalbinol from the seeds of Amorpha fruticosa L. Our data demonstrated that dalbinol inhibited the growth of HepG2, HepG2/ADM and Huh7 cells in a concentration-dependent manner. Pharmacological experiments also showed that dalbinol suppressed growth and induced apoptosis in these HCC cell lines in vitro. Furthermore, we found that dalbinol promoted β-catenin degradation, which was mediated by the ubiquitin-proteasome pathway. To summarize, our results illustrate that dalbinol inhibited HCC cell growth by facilitating β-catenin degradation through the ubiquitin-proteasome pathway. Hence, we propose that dalbinol will be a promising agent for the treatment of HCC subtypes with aberrant Wnt/β-catenin pathway activation.
Highlights
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide
The rise in the incidence of HCC is caused by the recent increase in hepatitis C virus (HCV) infection, a subtype of the hepatitis virus that is associated with human cancers [1]
To evaluate the cytotoxic effects of dalbinol, the Cell Counting Kit-8 (CCK-8) assay was performed after exposing cells to dalbinol or rotenone for 68 h
Summary
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. It ranks 6th in terms of global incidence, and is steadily increasing in Western countries. Aberrations in the canonical Wnt signaling pathway contribute to congenital malformations, osteoporosis and cancers [5,6,7], including hepatocellular carcinoma [8,9,10]. Low β-catenin levels are maintained through an ubiquitin-proteasome degradation pathway www.impactjournals.com/oncotarget following adenomatous polyposis coli (APC)-mediated transportation from the nucleus to the cytoplasm [11]. Phosphorylation at serines 33 and 37 creates a binding site for the E3 ubiquitin ligase β-TrCP, leading to β-catenin degradation [17]
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