Epigallocatechin-3-Gallate Inhibits Hepatoblastoma Growth by Reactivating the Wnt Inhibitor SFRP1

Abstract

Activation of Wnt signaling plays a central role in the formation of hepatoblastoma (HB), the most common pediatric liver cancer. Blocking this pathway with specific inhibitors is currently the target of various research endeavours. This study provides evidence that the naturally occurring flavonoid epigallocatechin-3-gallate (EGCG) is highly effective against HB growth through inhibition of Wnt signaling. We demonstrate that EGCG has a strong cytotoxic effect on HB cells in a time- and dose-dependent manner by impinging on cell viability, while leaving normal fibroblasts unaffected. Apoptotic features, including morphological changes, caspase 3 activity, and proteolytic cleavage of poly(ADP-ribose) polymerase, were frequently found in EGCG-treated HB cells, thereby suggesting involvement of the mitochondrial intrinsic apoptotic pathway. We furthermore show that EGCG effectively inhibits Wnt signaling, as evidenced by down-regulation of Wnt-responsive reporter gene activity and expression of the Wnt target genes MYC and CCND1. Interestingly, EGCG induced reexpression of the tumor suppressor gene SFRP1, which is transcriptionally silenced in HB cells and known to down-regulate Wnt signaling. Considering the lack of toxic effects on normal cells, EGCG should be preclinically validated as an adjuvant therapy in vivo with the ultimate goal of determining its efficacy in human trials.

ACKNOWLEDGMENTS

We are grateful to Nicole Stadler and Fatemeh Promoli for technical assistance. This work was supported by grants of the Friedrich Baur foundation, Munich (to Jan Gödeke); the Bettina Bräu foundation, Munich; the Horst Müggenburg foundation, Hamburg; and the Gänseblümchen-Voerde foundation, Voerde (to Roland Kappler). Jan Gödeke and Sarah Maier contributed equally to this article.