WM130 preferentially inhibits hepatic cancer stem-like cells by suppressing AKT/GSK3β/β-catenin signaling pathway
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Chen-Xu Ni1,*, Yang Qi1,*, Jin Zhang1,2,*, Ying Liu2, Wei-Heng Xu1, Jing Xu2, Hong-Gang Hu1, Qiu-Ye Wu1, Yan Wang1, Jun-Ping Zhang1
1School of Pharmacy, Second Military Medical University, Shanghai 200433, China
2Department of Pharmacy, Shanghai East Hospital, Tongji University, Shanghai 310000, China
*These authors have contributed equally to this work
Jun-Ping Zhang, email: email@example.com
Yan Wang, email: firstname.lastname@example.org
Keywords: matrine derivative, hepatocellular carcinoma, cancer stem-like cells, GSK3β, AKT
Received: January 18, 2016 Accepted: October 14, 2016 Published: October 22, 2016
The eradication of cancer stem cells (CSCs) is significant for cancer therapy and prevention. In this study, we evaluated WM130, a novel derivative of matrine, for its effect on CSCs using human hepatocellular carcinoma (HCC) cell lines, their sphere cells, and sorted EpCAM+ cells. We revealed that WM130 could not only inhibit proliferation and colony formation of HCC cells, but also suppress the expression of some stemness-related genes and up-regulate some mature hepatocyte marker genes, indicating a promotion of differentiation from CSCs to hepatocytes. WM130 also suppressed the proliferation of doxorubicin-resistant hepatoma cells, and markedly reduced the cells with CSC biomarker EpCAM. Moreover, WM130 suppressed HCC spheres, not only primary spheres but also subsequent spheres, indicating an inhibitory effect on self-renewal capability of CSCs. Interestingly, WM130 exhibited a remarkable inhibitory preference on HCC spheres and EpCAM+ cells rather than their parental HCC cells and EpCAM- cells respectively. In vivo, WM130 inhibited HCC xenograft growth, decreased the number of sphere-forming cells, and remarkably decreased the levels of EpCAM mRNA and protein in tumor xenografts. Better inhibitory effect was achieved by WM130 in combination with doxorubicin. Further mechanism study revealed that WM130 inhibited AKT/GSK3β/β-catenin signaling pathway. Collectively, our results suggest that WM130 remarkably inhibits hepatic CSCs, and this effect may via the down-regulation of the AKT/GSK3β/β-catenin pathway. These findings provide a strong rationale for the use of WM130 as a novel drug candidate in HCC therapy.
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