Abstract 5547: Anti-proliferative activity of hydnocarpin, a natural lignan, is associated with the inhibition of Wnt/β-catenin signaling pathway via axin turnover in colon cancer cells

Abnormal activation of the canonical Wnt/β-catenin pathway and up-regulation of the β-catenin/T-cell factor (TCF) response to transcriptional signaling play critical roles early in colorectal carcinogenesis. Therefore, the Wnt/β-catenin signaling is considered an attractive target for cancer chemotherapeutic of chemopreventive agents, natural compounds were evaluated for β-catenin-mediated transcriptional activity. Hydnocarpin (HC), a natural lignan from Lonicera japonica was identified as a promising candidate because it effectively inhibited β-catenin/TCF reporter gene (TOPflash) activity. HC also exhibited potent growth inhibition of SW480 human colon cancer cells. Further investigation of HC on the regulation of the Wnt/β-catenin signaling revealed that HC had minimal effect on GSKβ and CK1α, while the protein levels of both axin1 and axin2 were remarkably increased by HC treatment. In addition, the interaction of axin and β-catenin by HC was significantly increased as analyzed by immunoprecipitation assay. These events led to up-regulation of the β-catenin destruction complex formation and phosphorylation of β-catenin. To further explore the role of axin1 up-regulation by HC in the mechanism of action of Wnt inhibitory effects on SW480 cells, siRNA experiments were conducted. The growth inhibitory effects of HC on SW480 cells were abolished by axin1 siRNA, implying that HC inhibited the Wnt/β-catenin signaling in an axin-dependent fashion. These finding suggests that HC might be a novel Wnt inhibitor and has a potential of signaling regulator in β-catenin-mediated signaling pathways. Citation Format: Won Kyung KIM, Min Ai LEE, Hyen Joo PARK, Ji-Young HONG, Sam Sik KANG, Sang Kook LEE. Anti-proliferative activity of hydnocarpin, a natural lignan, is associated with the inhibition of Wnt/β-catenin signaling pathway via axin turnover in colon cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5547. doi:10.1158/1538-7445.AM2015-5547