GSK-3β governs inflammation-induced NFATc2 signaling hubs to promote pancreatic cancer progression

Sandra Baumgart, Nai Ming Chen, Jin San Zhang, Daniel D. Billadeau, Irina N. Gaisina, Alan P. Kozikowski, Shiv K. Singh, Daniel Fink, Philipp Ströbel, Caroline Klindt, Lizhi Zhang, William R. Bamlet, Alexander Koenig, Elisabeth Hessmann, Thomas M. Gress, Volker Ellenrieder, Albrecht Neesse

Research output: Contribution to journalArticlepeer-review

Abstract

We aimed to investigate the mechanistic, functional, and therapeutic role of glycogen synthase kinase 3β (GSK-3β) in the regulation and activation of the proinflammatory oncogenic transcription factor nuclear factor of activated T cells (NFATc2) in pancreatic cancer. IHC, qPCR, immunoblotting, immunofluorescence microscopy, and proliferation assays were used to analyze mouse and human tissues and cell lines. Protein-protein interactions and promoter regulation were analyzed by coimmunoprecipitation, DNA pulldown, reporter, and ChIP assays. Preclinical assays were performed using a variety of pancreatic cancer cells lines, xenografts, and a genetically engineered mouse model (GEMM). GSK-3β-dependent SP2 phosphorylationmediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3β also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation. For NFATc2-STAT3 complex formation, GSK-3β-mediated phosphorylation of STAT3 at Y705 is required to stimulate euchromatin formation of NFAT target promoters, such as cyclin-dependent kinase-6, which promotes tumor growth. Finally, preclinical experiments suggest that targeting the NFATc2-STAT3-GSK-3β module inhibits proliferation and tumor growth and interferes with inflammationinduced pancreatic cancer progression in KrasG12D mice. In conclusion, we describe a novel mechanism by which GSK-3b fine-tunes NFATc2 and STAT3 transcriptional networks to integrate upstream signaling events that govern pancreatic cancer progression and growth. Furthermore, the therapeutic potential of GSK-3β is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)491-502
Number of pages12
JournalMolecular cancer therapeutics
Volume15
Issue number3
DOIs
StatePublished - Mar 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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