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

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Jan 10

PMID 23301098

Citations 28

Authors

Heike Doppler

Geou-Yarh Liou

Peter Storz

Affiliations

Soon will be listed here.

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 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.

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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References

Kamitani T, Kito K, Nguyen H, Yeh E . Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein. J Biol Chem. 1997; 272(45):28557-62. DOI: 10.1074/jbc.272.45.28557. View

Trauzold A, Roder C, Sipos B, Karsten K, Arlt A, Jiang P . CD95 and TRAF2 promote invasiveness of pancreatic cancer cells. FASEB J. 2005; 19(6):620-2. DOI: 10.1096/fj.04-2984fje. View

Varfolomeev E, Blankenship J, Wayson S, Fedorova A, Kayagaki N, Garg P . IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007; 131(4):669-81. DOI: 10.1016/j.cell.2007.10.030. View

Cowell C, Yan I, Eiseler T, Leightner A, Doppler H, Storz P . Loss of cell-cell contacts induces NF-kappaB via RhoA-mediated activation of protein kinase D1. J Cell Biochem. 2009; 106(4):714-28. PMC: 4556359. DOI: 10.1002/jcb.22067. View

Karin M, Greten F . NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005; 5(10):749-59. DOI: 10.1038/nri1703. View

Bastea L, Doppler H, Balogun B, Storz P . Protein kinase D1 maintains the epithelial phenotype by inducing a DNA-bound, inactive SNAI1 transcriptional repressor complex. PLoS One. 2012; 7(1):e30459. PMC: 3262827. DOI: 10.1371/journal.pone.0030459. View

Vallabhapurapu S, Matsuzawa A, Zhang W, Tseng P, Keats J, Wang H . Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat Immunol. 2008; 9(12):1364-70. PMC: 2671996. DOI: 10.1038/ni.1678. View

Pan X, Arumugam T, Yamamoto T, Levin P, Ramachandran V, Ji B . Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells. Clin Cancer Res. 2008; 14(24):8143-51. PMC: 4403242. DOI: 10.1158/1078-0432.CCR-08-1539. View

Ghosh S, May M, Kopp E . NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998; 16:225-60. DOI: 10.1146/annurev.immunol.16.1.225. View

10.

Chandler N, Canete J, Callery M . Increased expression of NF-kappa B subunits in human pancreatic cancer cells. J Surg Res. 2004; 118(1):9-14. DOI: 10.1016/S0022-4804(03)00354-8. View

11.

Annunziata C, Davis R, Demchenko Y, Bellamy W, Gabrea A, Zhan F . Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 2007; 12(2):115-30. PMC: 2730509. DOI: 10.1016/j.ccr.2007.07.004. View

12.

Derudder E, Dejardin E, Pritchard L, Green D, Korner M, Baud V . RelB/p50 dimers are differentially regulated by tumor necrosis factor-alpha and lymphotoxin-beta receptor activation: critical roles for p100. J Biol Chem. 2003; 278(26):23278-84. DOI: 10.1074/jbc.M300106200. View

13.

Zarnegar B, Wang Y, Mahoney D, Dempsey P, Cheung H, He J . Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008; 9(12):1371-8. PMC: 2676931. DOI: 10.1038/ni.1676. View

14.

Nishina T, Yamaguchi N, Gohda J, Semba K, Inoue J . NIK is involved in constitutive activation of the alternative NF-kappaB pathway and proliferation of pancreatic cancer cells. Biochem Biophys Res Commun. 2009; 388(1):96-101. DOI: 10.1016/j.bbrc.2009.07.125. View

15.

Keats J, Fonseca R, Chesi M, Schop R, Baker A, Chng W . Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007; 12(2):131-44. PMC: 2083698. DOI: 10.1016/j.ccr.2007.07.003. View

16.

Wharry C, Haines K, Carroll R, May M . Constitutive non-canonical NFkappaB signaling in pancreatic cancer cells. Cancer Biol Ther. 2009; 8(16):1567-76. PMC: 2910422. DOI: 10.4161/cbt.8.16.8961. View

17.

Li X, Yang Y, Ashwell J . TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature. 2002; 416(6878):345-7. DOI: 10.1038/416345a. View

18.

Hunter A, LaCasse E, Korneluk R . The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis. 2007; 12(9):1543-68. DOI: 10.1007/s10495-007-0087-3. View

19.

Nakanishi C, Toi M . Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer. 2005; 5(4):297-309. DOI: 10.1038/nrc1588. View

20.

Baud V, Karin M . Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov. 2009; 8(1):33-40. PMC: 2729321. DOI: 10.1038/nrd2781. View