Z Gastroenterol 2015; 53 - KG118
DOI: 10.1055/s-0035-1559144

Activation of PP2A as druggable target in HCC therapy

H Curth 1, A Bowe 1, V Hoffmann 1, T Goeser 1, D Nierhoff 1
  • 1Universität Köln, Universitätsklinikum Köln, Abteilung für Gastroenterologie und Hepatologie, Köln, Deutschland

Background: Hepatocellular carcinoma (HCC) is one of the most common solid tumor entities worldwide and the third leading cause of cancer related death. For advanced stage disease, systemic pharmacotherapy is the only established therapy, targeting the oncogenic protein kinases pathways. However, chemotherapy still yields poor response rates and survival in those patients. Recently, it could be demonstrated, that activating the protein phosphatase pathways may have a therapeutic impact on various types of cancer.

Methods: The murine and human HCC cell lines Hepa 1 – 6, Hepa 129, HuH7, HepG2 and Hep3B were used for in vitro studies. Cells were treated with either direct (N-hexanoyl-D-sphingosine) or indirect (N,N-dimethylsphingosine, COG449) protein phosphatase 2A (PP2A) activators and cell proliferation, apoptosis and necroptosis were assessed by neutral red staining. PP2A activity was assessed by coimmunoprecipitation and consecutive activity assay. Regulation of the PP2A inhibitory proteins I1PP2A, I2PP2A and CIP2A, as well as signal transduction pathways, were analysed by Western Blot and qRT-PCR. Human HCC tissue samples, obtained from surgical resection were tested for the above mentioned proteins (n = 22) in relation to tumor-free surrounding liver tissue and correlated with their Ki67 expression.

Results: The activity of the PP2A inhibitory proteins was markedly up-regulated in mouse and human HCC cell lines. Furthermore, pharmacologic inactivation of I2PP2A, as well as direct or indirect activation of PP2A, led to an AKT mediated growth suppression of HCC cells in vitro, which was at least partly dependent on necroptosis induction. In human HCC, increased levels of I1PP2A, I2PP2A and CIP2A were furthermore significantly correlated to cell proliferation.

Conclusions: Our data demonstrate that the protein phosphatase pathway is a potential novel treatment target in HCC and PP2A activators represent possible agents in the future therapy of this malignancy.