The regulation of constitutive NF-kappaB by glycogen synthase kinase-3 in pancreatic cancer.

摘要

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-kappaB. However, advancement of this therapeutic strategy is dependent on fully understanding the elusive mechanisms underlying constitutive NF-kappaB activity in pancreatic cancer. Glycogen synthase kinase-3 has previously been implicated in regulating pro-survival NF-kappaB signaling in pancreatic cancer cells through an unknown mechanism. Moreover, TGF-alpha activated kinase 1 (TAK1) is a known regulator of NF-kappaB activity in human cancers, but its role in pancreatic cancer has yet to be established. In this report, we characterize GSK-3-dependent NF-kappaB regulation in pancreatic cancer cells and provide initial evidence that GSK-3 facilitates constitutive IkappaB kinase (IKK) activity. Our data also indicates that TAK1 is active in pancreatic cancer and contributes to constitutive NF-kappaB activation. Importantly, GSK-3 may be functionally linked to IKK through the phosphorylation of TAK1 at serine 412. Collectively, we propose that constitutive NF-kappaB activity in pancreatic cancer cells is maintained by a novel GSK-3-TAK1-IKK signaling cascade. These data broadens our understanding of NF-kappaB regulation in pancreatic cancer and implicates GSK-3 and TAK1 as emerging therapeutic targets.