Abstract 2892: Glycogen synthase kinase-3α regulates cell proliferation in pancreatic cancer cells by regulating constitutive TAK1 and NF-κB signaling

Abstract

Abstract Pancreatic ductal adenocarinoma (PDA) represents the fourth leading cause of cancer-related deaths in the United States with a 5-year patient survival rate less than 5%. The transcription factor NF-κB is constitutively active and contributes to cell survival and cancer therapy resistance in these tumors. Previous reports have linked constitutive IκB kinase (IKK) activity to canonical NF-κB signaling in human pancreatic cancer cells. However, the signaling events that drive IKK activity remain poorly understood. TGF-β activated kinase 1 (TAK1) is an established regulator of IKK activity and has been shown to be active in human cancer cell lines. Moreover, we previously reported that glycogen synthase kinase-3 (GSK-3) signals through IκB kinase (IKK) to facilitate downstream pro-survival NF-κB signaling and inhibition of GSK-3 suppressed cell proliferation in pancreatic cancer cells. Here, we investigate the status of TAK1 activity in pancreatic cancer cells and explore the potential regulation of constitutive TAK1-IKK signaling by GSK-3. We observed elevated levels of TAK1 phosphorylation and its association with TAB1 in a panel of pancreatic cancer cell lines. Genetic ablation of TAK1 in Panc-1 and MiaPaCa-2 cell lines resulted in decreased pro-survival NF-κB signaling. TAK1 was found to interact with GSK-3α in co-immunoprecipitation studies and both the genetic ablation and inhibition of GSK-3α suppressed NF-κB activity, TAK1 levels and growth of pancreatic cancer cells. We also observed reduction in the levels of TAB1 and TAB2, binding partners of TAK1, upon pharmacological inhibition of GSK-3. Additionally, pharmacological inhibition of GSK-3 significantly suppressed the levels of TAK1 and the growth of human pancreatic tumor explants in mice. Recently non-canonical or IKK- independent NF-κB signaling was also observed to be constitutively active and contributing to cell survival in pancreatic cancer cells. Preliminary data from si-RNA mediated knockdown studies suggests a positive regulation of non-canonical NF-κB signaling by GSK-3α. Overall, our data suggests that constitutive TAK1/TAB1-IKK and non-canonical NF-κB signaling in pancreatic cancer is driven by novel GSK-3α dependent mechanisms. These data provide new insight into our understanding of constitutive NF-κB regulation in pancreatic cancer and presents TAK1 as a potential new therapeutic target for this disease. Further investigation is required to understand the mechanism of GSK-3α-TAK1/TAB1 and GSK-3α-non canonical NF-κB regulation and their effect on pro-survival NF-κB signaling in pancreatic cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2892. doi:10.1158/1538-7445.AM2011-2892