Critical Role of NF-κB in Pancreatic Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2014 Dec 5

PMID 25473891

Citations 86

Authors

Lakshmi Prabhu

Rasika Mundade

Murray Korc

Patrick J Loehrer

Tao Lu

Affiliations

Soon will be listed here.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and in spite of intense efforts there are limited therapeutic options for patients with PDAC. PDACs harbor a high frequency of Kras mutations and other driver mutations that lead to altered signaling pathways and contribute to therapeutic resistance. Importantly, constitutive activation of nuclear factor κB (NF-κB) is frequently observed in PDAC. An increasing body of evidence suggests that both classical and non-classical NF-κB pathways play a crucial role in PDAC development and progression. In this review, we update the most recent advances regarding different aspects of NF-κB involvement in PDAC development and progression, emphasizing its potential as a therapeutic target and the need to discover pathway-specific cytosolic NF-κB regulators which could be used to design novel therapeutic strategies for PDAC.

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References

Aguirre A, Bardeesy N, Sinha M, Lopez L, Tuveson D, Horner J . Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 2003; 17(24):3112-26. PMC: 305262. DOI: 10.1101/gad.1158703. View

Ling J, Kang Y, Zhao R, Xia Q, Lee D, Chang Z . KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012; 21(1):105-20. PMC: 3360958. DOI: 10.1016/j.ccr.2011.12.006. View

Liou G, Doppler H, Necela B, Krishna M, Crawford H, Raimondo M . Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs. J Cell Biol. 2013; 202(3):563-77. PMC: 3734091. DOI: 10.1083/jcb.201301001. View

Rao C, Mohammed A, Janakiram N, Li Q, Ritchie R, Lightfoot S . Inhibition of pancreatic intraepithelial neoplasia progression to carcinoma by nitric oxide-releasing aspirin in p48(Cre/+)-LSL-Kras(G12D/+) mice. Neoplasia. 2012; 14(9):778-87. PMC: 3459273. DOI: 10.1593/neo.121026. View

Wang W, Abbruzzese J, Evans D, Larry L, Cleary K, Chiao P . The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res. 1999; 5(1):119-27. View

Carriere C, Gore A, Norris A, Gunn J, Young A, Longnecker D . Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions. Gastroenterology. 2011; 141(3):1091-101. PMC: 3163782. DOI: 10.1053/j.gastro.2011.05.041. View

Vidya Priyadarsini R, Senthil Murugan R, Maitreyi S, Ramalingam K, Karunagaran D, Nagini S . The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-κB inhibition. Eur J Pharmacol. 2010; 649(1-3):84-91. DOI: 10.1016/j.ejphar.2010.09.020. View

Gilabert M, Calvo E, Airoldi A, Hamidi T, Moutardier V, Turrini O . Pancreatic cancer-induced cachexia is Jak2-dependent in mice. J Cell Physiol. 2014; 229(10):1437-43. DOI: 10.1002/jcp.24580. View

Lu T, Tian L, Han Y, Vogelbaum M, Stark G . Dose-dependent cross-talk between the transforming growth factor-beta and interleukin-1 signaling pathways. Proc Natl Acad Sci U S A. 2007; 104(11):4365-70. PMC: 1810327. DOI: 10.1073/pnas.0700118104. View

10.

Wei H, Wang B, Miyagi M, She Y, Gopalan B, Huang D . PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB. Proc Natl Acad Sci U S A. 2013; 110(33):13516-21. PMC: 3746871. DOI: 10.1073/pnas.1311784110. View

11.

Doppler H, Liou G, Storz P . Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity. PLoS One. 2013; 8(1):e53676. PMC: 3536768. DOI: 10.1371/journal.pone.0053676. View

12.

Okayasu I, Ohkusa T, Kajiura K, Kanno J, Sakamoto S . Promotion of colorectal neoplasia in experimental murine ulcerative colitis. Gut. 1996; 39(1):87-92. PMC: 1383238. DOI: 10.1136/gut.39.1.87. View

13.

Karin M . Nuclear factor-kappaB in cancer development and progression. Nature. 2006; 441(7092):431-6. DOI: 10.1038/nature04870. View

14.

Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng W, Roels S . Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood. 2006; 109(8):3177-88. DOI: 10.1182/blood-2006-09-044974. View

15.

Bardeesy N, Aguirre A, Chu G, Cheng K, Lopez L, Hezel A . Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci U S A. 2006; 103(15):5947-52. PMC: 1458678. DOI: 10.1073/pnas.0601273103. View

16.

Preis M, Korc M . Signaling pathways in pancreatic cancer. Crit Rev Eukaryot Gene Expr. 2011; 21(2):115-29. DOI: 10.1615/critreveukargeneexpr.v21.i2.20. View

17.

Lu T, Stark G . Cytokine overexpression and constitutive NFkappaB in cancer. Cell Cycle. 2004; 3(9):1114-7. View

18.

Lu T, Jackson M, Singhi A, Kandel E, Yang M, Zhang Y . Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NFkappaB. Proc Natl Acad Sci U S A. 2009; 106(38):16339-44. PMC: 2736141. DOI: 10.1073/pnas.0908560106. View

19.

Maniati E, Bossard M, Cook N, Candido J, Emami-Shahri N, Nedospasov S . Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. J Clin Invest. 2011; 121(12):4685-99. PMC: 3225987. DOI: 10.1172/JCI45797. View

20.

Lowenfels A, Maisonneuve P, Cavallini G, Ammann R, Lankisch P, Andersen J . Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993; 328(20):1433-7. DOI: 10.1056/NEJM199305203282001. View