Maintenance of constitutive NF-κB activity by glycogen synthase kinase-3 and IKK in pancreatic cancer Free

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Pancreatic cancer is well-known for its aggressive metastatic potential and resistance to conventional chemotherapies. Constitutively active NF-κB is part of the complex signaling pathway that contributes to pancreatic carcinogenesis. The signaling required for the maintenance of NF-κB activity in this disease is not well understood. There has been increasing evidence suggesting that glycogen synthase kinase-3 (GSK-3) may play a key role in regulating NF-κB activity in pancreatic cancer models. Nonetheless, the role GSK-3 plays in maintaining constitutive NF-κB activity still remains to be characterized. In this report, we utilize thepancreatic cancer cell lines Panc-1 and MiaPaCa-2 to examine specific roles of GSK-3 and IKK isoforms in regulating NF-κB activity and subsequent cell proliferation. We show using GSK-3-specific knock-down that GSK-3α plays a predominant role over GSK-3β in regulating basal NF-κB DNA binding, reporter activity, and cell growth. Notably, the disruption of IKKα was also more effective in suppressing constitutive NF-κB activity and cell proliferation when compared to IKKβ. We show that both GSK-3 isoforms and IKKα are aberrantly localized in the nucleus. Moreover, GSK-3α and IKKα co-immunoprecipitate from nuclear extracts which suggest a potential mechanism for maintaining constitutive NF-κB activity. These data provide new insight into the specific roles GSK-3 and IKK isoforms play in regulating NF-κB activity and proliferation. Furthermore, our data implicates GSK-3α and IKKα as potential therapeutic targets for pancreatic cancer.