The regulation of constitutive NF-κB activity by glycogen synthase kinase-3 in pancreatic cancer Public Deposited

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  • March 22, 2019
Creator
  • Wilson, Willie, III
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • The development of pancreatic cancer chemotherapy has evolved into targeting the complex signaling pathways associated with disease progression. Recent focus has been made on targeting the constitutive activation of the transcription factor, NF-κB. However, advancement of this therapeutic strategy is dependent on fully understanding the elusive mechanisms underlying constitutive NF-κB activity in pancreatic cancer. Glycogen synthase kinase-3 has previously been implicated in regulating pro-survival NF-κB signaling in pancreatic cancer cells through an unknown mechanism. Moreover, TGF-β activated kinase 1 (TAK1) is a known regulator of NF-κB activity in human cancers, but its role in pancreatic cancer has yet to be established. In this report, we characterize GSK-3-dependent NF-κB regulation in pancreatic cancer cells and provide initial evidence that GSK-3 facilitates constitutive IκB kinase (IKK) activity. Our data also indicates that TAK1 is active in pancreatic cancer and contributes to constitutive NF-κB activation. Importantly, GSK-3 may be functionally linked to IKK through the phosphorylation of TAK1 at serine 412. Collectively, we propose that constitutive NF-κB activity in pancreatic cancer cells is maintained by a novel GSK-3-TAK1-IKK signaling cascade. These data broadens our understanding of NF-κB regulation in pancreatic cancer and implicates GSK-3 and TAK1 as emerging therapeutic targets.
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  • In Copyright
Advisor
  • Baldwin, Albert
Degree granting institution
  • University of North Carolina at Chapel Hill
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