Abstract
AimsYes-associated protein (YAP), a downstream protein in the Hippo signaling pathway, plays an important role in tumor proliferation, including in hepatocellular carcinoma (HCC). α-hederin, a monodesmosidic triterpenoid saponin isolated from Fructus akebiae, displayed anti-cancer effects on several cancer cell lines but the precise mechanism has not been ascertained. In the present study, we explored the effects of α-hederin on cell proliferation and apoptosis in human HCC cell lines and the underlying mechanisms.Main MethodCell proliferation and apoptosis were assessed using 5-ethynyl-2’-deoxyuridine staining, colony formation, flow cytometry. The expression patterns of components of Hippo signaling pathway and apoptotic genes were further examined via RT-qPCR and immunoblotting. A xenograft tumor model in nude mice was used to evaluate the anti-HCC effects of α-hederin in vivo.Resultsα-hederin promoted the apoptosis and inhibited the proliferation of SMMC-7721 and HepG2 cells in vitro, and remarkably inhibited the tumor size and weight in the xenograft mouse model. Additionally, α-hederin increased the expression of pro-apoptosis proteins and suppressed the expression of anti-apoptosis proteins. Moreover, α-hederin treatment upregulated the expression of Hippo signaling pathway-related proteins and genes, while, effectively reduced the level of nuclear YAP, which resulted in the inhibition of proliferation and the induction of apoptosis of HCC cells. Finally, the effects of α-hederin on HCC cell proliferation and apoptosis were alleviated by XMU-MP-1, a Mst1/2 inhibitor in vitro.SignificanceWe identified α-hederin is a novel agonist of Hippo signaling pathway and possesses an anti-HCC efficacy through inhibiting YAP activity.
Highlights
Liver cancer is one of the most malignant cancers with poor prognosis which already be the third leading cause of cancerrelated death worldwide
We identified a-hederin is a novel agonist of Hippo signaling pathway and possesses an anti-hepatocellular carcinoma (HCC) efficacy through inhibiting Yes-associated protein (YAP) activity
The results revealed that the expression of Bax and cleaved-caspase3 were obviously increased by a-hederin treatment, while the expression of Bcl2 and caspase-3 in HepG2 and SMMC-7721 cells were significantly decreased in a dose-dependent manner (Figure 2B)
Summary
Liver cancer is one of the most malignant cancers with poor prognosis which already be the third leading cause of cancerrelated death worldwide. The Hippo signaling pathway was originally identified in Drosophila melanogaster and later in mammals [4, 5]. Several studies have proposed that a-hederin had an anti-cancer activity It inhibited interleukin 6–induced epithelial–mesenchymal transition in colon cancer cells and induced apoptosis in non-small cell lung cancer by increasing the killing effect of Tax [15, 16]. Researchers reported that a-hederin could induce apoptosis of HCC cells via the mitochondrial pathway mediated by increased intracellular ROS [17]. Based on the pretesting research, we found a-hederin could induce cell death in several hepatoma cells, so we speculate that Hippo signaling pathway might be involved in this mechanism. We evaluated the effect of a-hederin on HCC proliferation in vivo and in vitro and explored the underlying molecular mechanism through investigating Hippo-YAP signaling pathway
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