Mechanismen der GSK-3-Beta-vermittelten Regulation des onkogenen Transkriptionsfaktors NFATc2 im Pankreaskarzinom

GSK-3-Beta is a multifunctional kinase which is deregulated in many diseases, such as diabetes, Alzheimers’s disease or cancer. It was originally considered to be a tumor suppressor due to its implication in the Wnt/-catenin signaling pathway. Recent studies however revealed a crucial pro-proliferative role in pancreatic cancer which is accompanied by an aggressive phenotype. GSK-3 is moreover a main modulator of the Calcineurin/NFAT signaling pathway. Thereby, it serves to phosphorylate NFAT proteins in the nucleus in order to induce their nuclear export. Own previous works could identify several crucial NFATc2-mediated mechanisms of pancreatic tumor growth stimulation. However, there is rare evidence about upstream regulatory pathways targeting NFATc2 metabolism in cancer. The aim of this study was to assess a potential GSK-3-Beta-NFATc2 interaction in pancreatic cancer and to evaluate the use of GSK-3-Beta inhibitors to specifically target NFATc2. Herein, we identified a novel phosphorylation-dependent GSK-3-Beta-NFATc2 stabilization pathway which significantly contributes to pancreatic cancer growth. Mechanistically, we found that GSK-3-Beta phosphorylates three conserved serines in the SP2 region of NFATc2 and thereby preserves a rapid degradation in the nucleus. By sitedirected mutagenesis, we could furthermore show that constitutive phosphorylation of NFATc2 accelerates tumor growth in vitro and in vivo. In addition, we identified STAT3 as a partner of NFATc2 and showed for the first time, that GSK-3-Beta stabilizes the interaction of NFATc2 with the oncogenic transcription factor and that this in turn enhances transcriptional activity on an NFAT-responsive promoter. Taken together this study reveals an oncogenic role of GSK-3-Beta in pancreatic cancer which is carried by a multi-faceted regulation of the transcription factor NFATc2. On the one hand, NFATc2 protein stability is strengthened by SP2 phosphorylation and on the other hand, transcriptional activity is stabilized independent of SP2 phosphorylation by recruiting a nuclear NFATc2-STAT3 complex. In summary, this novel oncogenic pathway provides further mechanistic insights into pancreatic cancer and opens new therapeutic prospects.