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Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity.

Doppler H, Liou GY, Storz P.

PLoS One. 2013;8(1):e53676.

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida, United States of America.

 

Abstract

BACKGROUND:

Increased levels of NF-κB are hallmarks of pancreatic ductal adenocarcinoma (PDAC) and both classical and alternative NF-κB activation pathways have been implicated.

METHODOLOGY/PRINCIPAL FINDINGS:

Here we show that activation of the alternative pathway is a source for the high basal NF-κB activity in PDACcell 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 celllines. Such upregulation of NIK expression and activity levels relays to increased proliferation and anchorage-independent growth, but not migration or survival of PDAC cells.

CONCLUSIONS/SIGNIFICANCE:

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.

 

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Additional Information

Doppler H, Liou G-Y, Storz P. Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity. PLoS One 2013; 8:e53676. PMCID:PMC3536768.

 

Due to its late diagnosis pancreatic cancer is difficult to treat and effective therapies are lacking. In this publication the authors demonstrate the importance of NF-κB-inducing kinase (NIK) in maintaining the high basal activity of the alternative NF-κB pathway in pancreatic cancer to increase cancer cell proliferation and tumorigenicity.  Constitutive signaling of NIK in pancreatic cancer cell lines is facilitated by downregulation of TRAF2 protein expression. The findings obtained with cell lines correlated with reverse expression of NIK and TRAF2 in human tissue samples. The data suggest novel possibilities for therapeutic intervention by targeting the alternative NF-κB pathway. This may be achieved by development of small molecule inhibitors for the kinases NIK and IκB kinase {Alpha} (IKK{Alpha}), and application alone or in combination with currently-used drugs.

 

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