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Okadaic acid activates Wnt/β-catenin-signaling in human HepaRG cells

Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Strasse 8-10, Berlin, Germany
Dietrich, Jessica;
Affiliation
SIGNATOPE GmbH, Reutlingen, Germany
Sommersdorf, Cornelia;
Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Strasse 8-10, Berlin, Germany
Gohlke, Svenja;
Affiliation
SIGNATOPE GmbH, Reutlingen, Germany
Poetz, Oliver;
Affiliation
NMI Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen, Germany
Traenkle, Bjoern;
Affiliation
NMI Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen, Germany
Rothbauer, Ulrich;
Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Strasse 8-10, Berlin, Germany
Hessel-Pras, Stefanie;
Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Strasse 8-10, Berlin, Germany
Lampen, Alfonso;
Affiliation
Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Strasse 8-10, Berlin, Germany
Braeuning, Albert

The lipophilic phycotoxin okadaic acid (OA) occurs in the fatty tissue and hepatopancreas of filter-feeding shellfish. The compound provokes the diarrhetic shellfish poisoning (DSP) syndrome after intake of seafood contaminated with high levels of the DSP toxin. In animal experiments, long-term exposure to OA is associated with an elevated risk for tumor formation in different organs including the liver. Although OA is a known inhibitor of the serine/threonine protein phosphatase 2A, the mechanisms behind OA-induced carcinogenesis are not fully understood. Here, we investigated the influence of OA on the β-catenin-dependent Wnt-signaling pathway, addressing a major oncogenic pathway relevant for tumor development. We analyzed OA-mediated effects on β-catenin and its biological function, cellular localization, post-translational modifications, and target gene expression in human HepaRG hepatocarcinoma cells treated with non-cytotoxic concentrations up to 50 nM. We detected concentration- and time-dependent effects of OA on the phosphorylation state, cellular redistribution as well as on the amount of transcriptionally active β-catenin. These findings were confirmed by quantitative live-cell imaging of U2OS cells stably expressing a green fluorescent chromobody which specifically recognize hypophosphorylated β-catenin. Finally, we demonstrated that nuclear translocation of β-catenin mediated by non-cytotoxic OA concentrations results in an upregulation of Wnt-target genes. In conclusion, our results show a significant induction of the canonical Wnt/β-catenin-signaling pathway by OA in human liver cells. Our data contribute to a better understanding of the molecular mechanisms underlying OA-induced carcinogenesis.

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