Abstract
Evodiamine is one of the main components isolated from Evodia rutaecarpa, and it has been reported to exert inhibitory effects on cancers by anti-proliferative and apoptosis-inducing activities. Although the anti-cancer activity of evodiamine has been identified, the precise mechanisms of this action remain obscure. While previous studies indicated that evodiamine exerts anti-tumor effects through inhibiting β-catenin activity, and WW domain-containing oxidoreductase (WWOX) regulates β-catenin accumulation in cytoplasm, the effects of evodiamine on the expression of WWOX are still unknown. In this study, we provide evidence that evodiamine dose- and time-dependently inhibits both Mus musculus and Homo sapiens hepatocellular carcinoma (HCC) cells, as well as Hepa1-6 and HepG2 cell proliferation. We further tested the therapeutic effects of evodiamine in Hepa1-6 hepatoma-bearing mice, and we found that treatment of evodiamine by oral gavage significantly decreased the tumor size of the mice. Moreover, the expressions of WWOX were dose-dependently increased in HCC cell lines as well as in Hepa1-6 hepatoma-bearing mice after the treatment with evodiamine. Knockdown of WWOX in HepG2 and Hepa1-6 cells diminished the effects of evodiamine on the inhibitory effect of cancer cell growth, indicating that evodiamine induced anti-cancer activity through a WWOX-dependent pathway. As such, evodiamine activated WWOX to exert an anti-HCC activity, and might be a potential therapeutic or preventive candidate for HCC treatment.
Highlights
Hepatocellular carcinoma (HCC) is the most predominant type of primary liver cancer, and the second leading cause of cancer-related mortality worldwide [1]
After the evodiamine treatment at a dose of 0.1 μM, we found a slight decrease in cell proliferation in Hepa1-6 cells
We found that evodiamine decreased the proliferation of Hepa1-6 cells, the mechanism by which evodiamine induced cell toxicity or cell arrest was still obscure
Summary
Hepatocellular carcinoma (HCC) is the most predominant type of primary liver cancer, and the second leading cause of cancer-related mortality worldwide [1]. Radiofrequency ablation, surgical resection, and liver transplantation are the primary curative treatments for HCC. Effective treatment for advanced HCC remains a major challenge, and new agents are needed for advanced. WWOX has been reported to be downregulated in HCC cell lines as well as in primary HCC tissues, and WWOX is implicated in the Wnt/β-catenin pathway, which is frequently affected in HCC [4,5,6]. In HCC, the downregulation of WWOX is associated with β-catenin accumulation in cytoplasm, and β-catenin will subsequently translocate into the nucleus and activate Wnt/β-catenin target genes [4]. The activation of the Wnt/β-catenin signaling pathway will enhance the proliferation and cell-cycle progression of HCC [7]. The activation of WWOX is a novel strategy for the treatment of HCC
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