Bruceine D inhibits hepatocellular carcinoma growth by targeting β-catenin/jagged1 pathways.

Hepatocellular carcinoma (HCC) is known for high mortality and limited available treatments. Aberrant activation of the Wnt and Notch signaling pathways is critical to liver carcinogenesis and progression. Here, we identified a small molecule, bruceine D (BD), as a Notch inhibitor, using an RBP-Jκ-dependent luciferase-reporter system. BD significantly inhibited liver tumor growth and enhanced the therapeutic effects of sorafenib in various murine HCC models. Mechanistically, BD promotes proteasomal degradation of β-catenin and the depletion of its nuclear accumulation, which in turn disrupts the Wnt/β-catenin-dependent transcription of the Notch ligand Jagged1 in HCC. Our findings provide important information about a novel Wnt/Notch crosstalk inhibitor that is synergistic with sorafenib for treatment of HCC, and therefore have high clinical impact.

Cheng Z ，Yuan X ，Qu Y ，Li X ，Wu G ，Li C ，Zu X ，Yang N ，Ke X ，Zhou J ，Xie N ，Xu X ，Liu S ，Shen Y ，Li H ，Zhang W ... -  《-》

Inhibition of the Wnt/β-catenin signaling pathway improves the anti-tumor effects of sorafenib against hepatocellular carcinoma.

Sorafenib, a multikinase inhibitor, is currently the only approved drug for advanced hepatocellular carcinoma (HCC). The current study tested the hypothesis whether inhibition of the Wnt/β-catenin signaling pathway could improve the anti-tumor effects of sorafenib in HCC. ICG-001, a small molecule which blocks the interaction of β-catenin with its transcriptional coactivator CBP, dose-dependently enhanced the growth-suppressive and apoptosis-induction effects of sorafenib in multiple HCC cell lines. Downregulation of β-catenin by RNA interference increased sorafenib sensitivity, whereas overexpression of β-catenin reduced sorafenib sensitivity in Huh7 cells. The sorafenib-sensitization effect of short hairpin RNA (shRNA)-mediated β-catenin downregulation in Huh7 cells was attenuated by β-catenin overexpression. Mechanistically, sorafenib combined with ICG-001 or shRNA-mediated β-catenin downregulation augmented the induction of apoptosis, and resulted in a significant downregulation of Mcl-1 in HCC cells. In Huh7 cell mouse xenograft model, the combination of ICG-001 and sorafenib showed a more significant growth-retarding effect than single agent treatment of sorafenib or ICG-001. Our data indicate that inhibition of the Wnt/β-catenin signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo.

Lin HH ，Feng WC ，Lu LC ，Shao YY ，Hsu CH ，Cheng AL ... -  《-》

Targeting KDM1A attenuates Wnt/β-catenin signaling pathway to eliminate sorafenib-resistant stem-like cells in hepatocellular carcinoma.

Use of the tyrosine kinase inhibitor sorafenib in patients with advanced hepatocellular carcinoma (HCC) is often hindered by the development of resistance, which has been recently shown to be associated with the emergence of a cancer stem cell (CSC) subpopulation. However, it remains largely unknown whether epigenetic mechanisms, especially histone posttranslational modifications, are causally linked to the maintenance of stem-like properties in sorafenib-resistant HCC. In this study, we report that the activity of lysine-specific histone demethylase 1A (KDM1A or LSD1) is required for the emergence of cancer stem cells following prolonged sorafenib treatment. As such, KDM1A inhibitors, such as pargyline and GSK2879552, dramatically suppress stem-like properties of sorafenib-resistant HCC cells. Mechanistically, KDM1A inhibitors derepress the expression of multiple upstream negative regulators of the Wnt signaling pathway to downregulate the β-catenin pathway. More importantly, KDM1A inhibition resensitizes sorafenib-resistant HCC cells to sorafenib in vivo, at least in part through reducing a CSC pool, suggesting a promising opportunity for this therapeutic combination. Together, these findings suggest that KDM1A inhibitors may be utilized to alleviate acquired resistance to sorafenib, thus increasing the therapeutic efficacy of sorafenib in HCC patients.

Huang M ，Chen C ，Geng J ，Han D ，Wang T ，Xie T ，Wang L ，Wang Y ，Wang C ，Lei Z ，Chu X ... -  《-》

PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation.

Liu Y ，Ye X ，Zhang JB ，Ouyang H ，Shen Z ，Wu Y ，Wang W ，Wu J ，Tao S ，Yang X ，Qiao K ，Zhang J ，Liu J ，Fu Q ，Xie Y ... -  《-》

Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells.

Ma L ，Wang X ，Jia T ，Wei W ，Chua MS ，So S ... -  《Oncotarget》