Downregulation of TRAF2 Mediates NIK-Induced Pancreatic Cancer Cell Proliferation and Tumorigenicity

• DOI: 10.1371/journal.pone.0053676
• Publication Date: 2013-01-04T00:52:37Z
• Authors: Heike Döppler; Geou-Yarh Liou; Peter Storz
• Keywords: 0301 basic medicine; Proteasome Endopeptidase Complex; Science; Down-Regulation; Tetrazolium Salts; Protein Serine-Threonine Kinases; 03 medical and health sciences; NF-kappa B p52 Subunit; Cell Movement; Cell Line, Tumor; Humans; Cell Proliferation; Cell Nucleus; Chemotaxis; Q; R; TNF Receptor-Associated Factor 2; 3. Good health; Gene Expression Regulation, Neoplastic; Pancreatic Neoplasms; Agar; Thiazoles; NF-kappaB-Inducing Kinase; Medicine; Research Article; Carcinoma, Pancreatic Ductal; Protein Binding

Increased levels of NF-κB are hallmarks of pancreatic ductal adenocarcinoma (PDAC) and both classical and alternative NF-κB activation pathways have been implicated.Here we show that activation of the alternative pathway is a source for the high basal NF-κB activity in PDAC cell lines. Increased activity of the p52/RelB NF-κB complex is mediated through stabilization and activation of NF-κB-inducing kinase (NIK). We identify proteasomal downregulation of TNF receptor-associated factor 2 (TRAF2) as a mechanism by which levels of active NIK are increased in PDAC cell lines. Such upregulation of NIK expression and activity levels relays to increased proliferation and anchorage-independent growth, but not migration or survival of PDAC cells.Rapid growth is one characteristic of pancreatic cancer. Our data indicates that the TRAF2/NIK/NF-κB2 pathway regulates PDAC cell tumorigenicity and could be a valuable target for therapy of this cancer.