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

Abstract

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.

• Authors: Jessica Dietrich, Cornelia Sommersdorf, Svenja Gohlke, Oliver Poetz, Bjoern Traenkle, Ulrich Rothbauer, Stefanie Hessel-Pras, Alfonso Lampen, Albert Braeuning
• Journal: Archives of toxicology (Arch Toxicol) Vol. 93 Issue 7 Pg. 1927-1939 (07 2019) ISSN: 1432-0738 [Electronic] Germany
• PMID: 31115591 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CTNNB1 protein, human
• Carcinogens
• beta Catenin
• Okadaic Acid

Topics

• Carcinogens (administration & dosage, toxicity)
• Carcinoma, Hepatocellular (metabolism)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Humans
• Liver Neoplasms (metabolism)
• Okadaic Acid (administration & dosage, toxicity)
• Phosphorylation (drug effects)
• Time Factors
• Up-Regulation (drug effects)
• Wnt Signaling Pathway (drug effects, genetics)
• beta Catenin (genetics, metabolism)