Archives of Toxicology

, Volume 93, Issue 7, pp 1927–1939 | Cite as

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

  • Jessica Dietrich
  • Cornelia Sommersdorf
  • Svenja Gohlke
  • Oliver Poetz
  • Bjoern Traenkle
  • Ulrich Rothbauer
  • Stefanie Hessel-PrasEmail author
  • Alfonso Lampen
  • Albert Braeuning
Molecular Toxicology


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.


liver toxicity Okadaic acid TCF/LEF-responsive genes Tumor promotion Wnt-signaling pathway 



Adenomatous polyposis coli




Casein kinase 1α


Cytochrome P450


Dulbecco’s modified Eagle’s medium


Dimethyl sulfoxide


Diarrhetic shellfish poisoning


E-cadherin cytosolic tail


Fetal bovine serum


Glycogen synthase kinase 3β




Inhibitor of β-catenin


Lymphoid enhancer factor


3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


Okadaic acid


Phosphate-buffered saline


Positive control


Serine/threonine protein phosphatase


Quantitative real-time reverse transcriptase polymerase chain reaction


Solvent control


Standard deviation


Serum-free assay medium




Tris-buffered saline with Tween 20


T-cell factor



This work was supported by the German Research Foundation (Grant no LA 1177/11-1) and by the German Federal Institute for Risk Assessment (Grant no. 1322-662).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

204_2019_2489_MOESM1_ESM.docx (85 kb)
Supplementary material 1 (DOCX 85 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jessica Dietrich
    • 1
  • Cornelia Sommersdorf
    • 2
  • Svenja Gohlke
    • 1
  • Oliver Poetz
    • 2
  • Bjoern Traenkle
    • 3
    • 4
  • Ulrich Rothbauer
    • 3
    • 4
  • Stefanie Hessel-Pras
    • 1
    Email author
  • Alfonso Lampen
    • 1
  • Albert Braeuning
    • 1
  1. 1.Department of Food SafetyGerman Federal Institute for Risk AssessmentBerlinGermany
  2. 2.SIGNATOPE GmbHReutlingenGermany
  3. 3.NMI Natural and Medical Sciences Institute at the University of TuebingenReutlingenGermany
  4. 4.Eberhard Karls University Tuebingen, Pharmaceutical BiotechnologyTuebingenGermany

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