Abstract
Dysregulation of the Wnt/β-catenin signaling pathway is involved in the development of human hepatocellular carcinoma and has thus emerged as a therapeutic target for this malignant tumor. In this study, we employed sensitive cell-based assays to identify aplykurodin A isolated from Aplysia kurodai as an antagonist of Wnt/β-catenin signaling. Aplykurodin A inhibited β-catenin responsive transcription, which was stimulated by a Wnt3a-conditioned medium or a glycogen synthase kinase 3β inhibitor by accelerating intracellular β-catenin degradation. Aplykurodin A downregulated the level of oncogenic β-catenin and decreased the expression of β-catenin-dependent gene, leading to inhibition of human hepatoma Hep3B and SNU475 cell proliferation. Moreover, apoptosis and autophagy were elicited by aplykurodin A, as indicated by an increase the number of Annexin V-FITC-stained cells and the formation of microtubule-associated protein 1 light chain 3 puncta, respectively, in Hep3B and SNU475 cells. Our findings suggest that aplykurodin A provides a novel therapeutic strategy for human hepatocellular carcinoma via stimulation of oncogenic β-catenin degradation.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-mediated mortality worldwide [1]
Our findings suggest that aplykurodin A provides a novel therapeutic strategy for human hepatocellular carcinoma via stimulation of oncogenic β-catenin degradation
These results indicate that aplykurodin A is a specific antagonist of
Summary
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-mediated mortality worldwide [1]. Recent therapies for this malignancy rely on surgical resection, by which only early stage HCC patients can be cured [2]; current diagnosis for HCC often fails to sense the early stage HCC [3]. Sorafenib, an inhibitor of receptor tyrosine kinase, has been used for the systemic treatment of advanced HCC, but most of patients do not exhibit the desired response to this therapeutics [4]. It is still necessary to develop new therapeutic strategies that are based on defined molecular lesions.
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