Journal
MOLECULAR CANCER THERAPEUTICS
Volume 15, Issue 3, Pages 491-502Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-15-0309
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Funding
- NCI Pancreatic Cancer SPORE grant [P50CA102701]
- Max Eder Fellowship Deutsche Krebshilfe [110972]
- National Natural Science Foundation of China [81472601]
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We aimed to investigate the mechanistic, functional, and therapeutic role of glycogen synthase kinase 3 beta (GSK-3 beta) 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-3 beta-dependent SP2 phosphorylationmediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3 beta also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation. For NFATc2-STAT3 complex formation, GSK-3 beta-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-3b module inhibits proliferation and tumor growth and interferes with inflammation-induced pancreatic cancer progression in Kras(G12D) mice. In conclusion, we describe a novel mechanism by which GSK3 beta 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-3 beta is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer. (C) 2016 AACR.
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