Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

Author(s): Cong Tang, Guodong Zhu*

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 3 , 2019

Become EABM
Become Reviewer


The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

Keywords: NF-κB, Syk, signaling pathway, cancer, therapy, tumor necrosis factor.

DiDonato JA, Mercurio F, Karin M. Nf-kappab and the link between inflammation and cancer. Immunol Rev 2012; 246: 379-400.
Kong L, Yang C, Yu L, et al. Pyrroloquinoline quinine inhibits rankl-mediated expression of nfatc1 in part via suppression of c-fos in mouse bone marrow cells and inhibits wear particle-induced osteolysis in mice. PLoS One 2013; 8: e61013.
Xia Y, Shen S, Verma IM. Nf-kappab, an active player in human cancers. Cancer Immunol Res 2014; 2: 823-30.
Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: The control of nf-[kappa]b activity. Annu Rev Immunol 2000; 18: 621-63.
Bonizzi G, Karin M. The two nf-kappab activation pathways and their role in innate and adaptive immunity. Trends Immunol 2004; 25: 280-8.
Kong L, Ma R, Yang X, et al. Psoralidin suppresses osteoclastogenesis in bmms and attenuates lps-mediated osteolysis by inhibiting inflammatory cytokines. Int Immunopharmacol 2017; 51: 31-9.
Wertz IE, Dixit VM. Signaling to nf-kappab: Regulation by ubiquitination. Cold Spring Harb Perspect Biol 2010; 2: a003350.
Hayden MS, Ghosh S. Signaling to nf-kappab. Genes Dev 2004; 18: 2195-224.
Greten FR, Karin M. The ikk/nf-kappab activation pathway-a target for prevention and treatment of cancer. Cancer Lett 2004; 206: 193-9.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140: 883-99.
Baud V, Karin M. Is nf-kappab a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 2009; 8: 33-40.
Yang C, Yu L, Kong L, et al. Pyrroloquinoline quinone (pqq) inhibits lipopolysaccharide induced inflammation in part via downregulated nf-kappab and p38/jnk activation in microglial and attenuates microglia activation in lipopolysaccharide treatment mice. PLoS One 2014; 9: e109502.
Li W, Kong LB, Li JT, et al. Mir-568 inhibits the activation and function of cd4(+) t cells and treg cells by targeting nfat5. Int Immunol 2014; 26: 269-81.
Yang X, Gao W, Wang B, et al. Picroside ii inhibits rankl-mediated osteoclastogenesis by attenuating the nf-kappab and mapks signaling pathway in vitro and prevents bone loss in lipopolysaccharide treatment mice. J Cell Biochem 2017; 118(12): 4479-86.
Kong L, Wang B, Yang X, et al. Picrasidine i from picrasma quassioides suppresses osteoclastogenesis via inhibition of rankl induced signaling pathways and attenuation of ros production. Cell Physiol Biochem 2017; 43: 1425-35.
Waterfield M, Jin W, Reiley W, Zhang M, Sun SC. Ikappab kinase is an essential component of the tpl2 signaling pathway. Mol Cell Biol 2004; 24: 6040-8.
Solan NJ, Miyoshi H, Carmona EM, Bren GD, Paya CV. Relb cellular regulation and transcriptional activity are regulated by p100. J Biol Chem 2002; 277: 1405-18.
Senftleben U, Cao Y, Xiao G, et al. Activation by ikkalpha of a second, evolutionary conserved, nf-kappa b signaling pathway. Science 2001; 293: 1495-9.
Pahl HL. Activators and target genes of rel/nf-kappab transcription factors. Oncogene 1999; 18: 6853-66.
Kim HJ, Hawke N, Baldwin AS. Nf-kappab and ikk as therapeutic targets in cancer. Cell Death Differ 2006; 13: 738-47.
Karin M. Nuclear factor-kappab in cancer development and progression. Nature 2006; 441: 431-6.
Kumar A, Takada Y, Boriek AM, Aggarwal BB. Nuclear factor-kappab: Its role in health and disease. J Mol Med (Berl) 2004; 82: 434-48.
Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving nf-kappab, lin28, let-7 microrna, and il6 links inflammation to cell transformation. Cell 2009; 139: 693-706.
Kawauchi K, Araki K, Tobiume K, Tanaka N. P53 regulates glucose metabolism through an ikk-nf-kappab pathway and inhibits cell transformation. Nat Cell Biol 2008; 10: 611-8.
Perkins ND. Integrating cell-signalling pathways with nf-kappab and ikk function. Nat Rev Mol Cell Biol 2007; 8: 49-62.
Beinke S, Robinson MJ, Hugunin M, Ley SC. Lipopolysaccharide activation of the tpl-2/mek/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by ikappab kinase-induced proteolysis of nf-kappab1 p105. Mol Cell Biol 2004; 24: 9658-67.
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144: 646-74.
Fan Y, Dutta J, Gupta N, Fan G, Gelinas C. Regulation of programmed cell death by nf-kappab and its role in tumorigenesis and therapy. Adv Exp Med Biol 2008; 615: 223-50.
Johnson RF, Witzel II, Perkins ND. P53-dependent regulation of mitochondrial energy production by the rela subunit of nf-kappab. Cancer Res 2011; 71: 5588-97.
Coopman PJ, Do MT, Barth M, et al. The syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature 2000; 406: 742-7.
Coopman PJ, Mueller SC. The syk tyrosine kinase: A new negative regulator in tumor growth and progression. Cancer Lett 2006; 241: 159-73.
Rickert RC. New insights into pre-bcr and bcr signalling with relevance to b cell malignancies. Nat Rev Immunol 2013; 13: 578-91.
Chen L, Monti S, Juszczynski P, et al. Syk-dependent tonic b-cell receptor signaling is a rational treatment target in diffuse large b-cell lymphoma. Blood 2008; 111: 2230-7.
Baudot AD, Jeandel PY, Mouska X, et al. The tyrosine kinase syk regulates the survival of chronic lymphocytic leukemia b cells through pkcdelta and proteasome-dependent regulation of mcl-1 expression. Oncogene 2009; 28: 3261-73.
Buchner M, Fuchs S, Prinz G, et al. Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Cancer Res 2009; 69: 5424-32.
Young RM, Hardy IR, Clarke RL, et al. Mouse models of non-hodgkin lymphoma reveal syk as an important therapeutic target. Blood 2009; 113: 2508-16.
Hatton O, Phillips LK, Vaysberg M, Hurwich J, Krams SM, Martinez OM. Syk activation of phosphatidylinositol 3-kinase/akt prevents htra2-dependent loss of x-linked inhibitor of apoptosis protein (xiap) to promote survival of epstein-barr virus+ (ebv+) b cell lymphomas. J Biol Chem 2011; 286: 37368-78.
Zhu Z, Hao D, Wang B, et al. Selection of surgical treatment approaches for cervicothoracic spinal tuberculosis: A 10-year case review. PLoS One 2018; 13: e0192581.
Gao W, Wang B, Hao D, et al. Surgical treatment of lower cervical fracture-dislocation with spinal cord injuries by anterior approach: 5- to 15-year follow-up. World Neurosurg 2018; 115: e137-45.
Yang H, He H, Dong Y. Card9 syk-dependent and raf-1 syk-independent signaling pathways in target recognition of candida albicans by dectin-1. Eur J Clin Microbiol Infect Dis 2011; 30: 303-5.
Glocker EO, Hennigs A, Nabavi M, et al. A homozygous card9 mutation in a family with susceptibility to fungal infections. N Engl J Med 2009; 361: 1727-35.
Gross O, Gewies A, Finger K, et al. Card9 controls a non-tlr signalling pathway for innate anti-fungal immunity. Nature 2006; 442: 651-6.
Underhill DM, Rossnagle E, Lowell CA, Simmons RM. Dectin-1 activates syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood 2005; 106: 2543-50.
Gringhuis SI, den Dunnen J, Litjens M, et al. Dectin-1 directs t helper cell differentiation by controlling noncanonical nf-kappab activation through raf-1 and syk. Nat Immunol 2009; 10: 203-13.
Chen L, Monti S, Juszczynski P, et al. Syk inhibition modulates distinct pi3k/akt- dependent survival pathways and cholesterol biosynthesis in diffuse large b cell lymphomas. Cancer Cell 2013; 23: 826-38.
Fang J, Wang Y, Lv X, Shen X, Ni X, Ding K. Structure of a beta-glucan from grifola frondosa and its antitumor effect by activating dectin-1/syk/nf-kappab signaling. Glycoconj J 2012; 29: 365-77.
Chapard C, Hohl D, Huber M. The role of the traf-interacting protein in proliferation and differentiation. Exp Dermatol 2012; 21: 321-6.
Takada Y, Aggarwal BB. Tnf activates syk protein tyrosine kinase leading to tnf-induced mapk activation, nf-kappab activation, and apoptosis. J Immunol 2004; 173: 1066-77.
Zhou Q, Geahlen RL. The protein-tyrosine kinase syk interacts with traf-interacting protein trip in breast epithelial cells. Oncogene 2009; 28: 1348-56.
Zhou F, Hu J, Ma H, Harrison ML, Geahlen RL. Nucleocytoplasmic trafficking of the syk protein tyrosine kinase. Mol Cell Biol 2006; 26: 3478-91.
Catz SD, Johnson JL. Transcriptional regulation of bcl-2 by nuclear factor kappa b and its significance in prostate cancer. Oncogene 2001; 20: 7342-51.
Tamatani M, Che YH, Matsuzaki H, et al. Tumor necrosis factor induces bcl-2 and bcl-x expression through nfkappab activation in primary hippocampal neurons. J Biol Chem 1999; 274: 8531-8.
Yamamoto K, Arakawa T, Ueda N, Yamamoto S. Transcriptional roles of nuclear factor kappa b and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in mc3t3-e1 cells. J Biol Chem 1995; 270: 31315-20.
Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS Jr. Nf-kappab controls cell growth and differentiation through transcriptional regulation of cyclin d1. Mol Cell Biol 1999; 19: 5785-99.
Stehlik C, de Martin R, Kumabashiri I, Schmid JA, Binder BR, Lipp J. Nuclear factor (nf)-kappab-regulated x-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis. J Exp Med 1998; 188: 211-6.
Roccaro AM, Vacca A, Ribatti D. Bortezomib in the treatment of cancer. Recent Patents Anticancer Drug Discov 2006; 1: 397-403.
Chariot A. The nf-kappab-independent functions of ikk subunits in immunity and cancer. Trends Cell Biol 2009; 19: 404-13.
Gilmore TD, Herscovitch M. Inhibitors of nf-kappab signaling: 785 and counting. Oncogene 2006; 25: 6887-99.
Shangary S, Wang S. Small-molecule inhibitors of the mdm2-p53 protein-protein interaction to reactivate p53 function: A novel approach for cancer therapy. Annu Rev Pharmacol Toxicol 2009; 49: 223-41.
Mayo MW, Madrid LV, Westerheide SD, et al. Pten blocks tumor necrosis factor-induced nf-kappa b-dependent transcription by inhibiting the transactivation potential of the p65 subunit. J Biol Chem 2002; 277: 11116-25.
Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP, Baldwin AS. Akt-dependent regulation of nf-kappab is controlled by mtor and raptor in association with ikk. Genes Dev 2008; 22: 1490-500.
Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin AS Jr, Mayo MW. Akt suppresses apoptosis by stimulating the transactivation potential of the rela/p65 subunit of nf-kappab. Mol Cell Biol 2000; 20: 1626-38.
Buss H, Dorrie A, Schmitz ML, et al. Phosphorylation of serine 468 by gsk-3beta negatively regulates basal p65 nf-kappab activity. J Biol Chem 2004; 279: 49571-4.
Barre B, Perkins ND. The skp2 promoter integrates signaling through the nf-kappab, p53, and akt/gsk3beta pathways to regulate autophagy and apoptosis. Mol Cell 2010; 38: 524-38.
Guma M, Stepniak D, Shaked H, et al. Constitutive intestinal nf-kappab does not trigger destructive inflammation unless accompanied by mapk activation. J Exp Med 2011; 208: 1889-900.
Greten FR, Eckmann L, Greten TF, et al. Ikkbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004; 118: 285-96.
Barre B, Perkins ND. A cell cycle regulatory network controlling nf-kappab subunit activity and function. EMBO J 2007; 26: 4841-55.
Rocha S, Martin AM, Meek DW, Perkins ND. P53 represses cyclin d1 transcription through down regulation of bcl-3 and inducing increased association of the p52 nf-kappab subunit with histone deacetylase 1. Mol Cell Biol 2003; 23: 4713-27.
Westerheide SD, Mayo MW, Anest V, Hanson JL, Baldwin AS Jr. The putative oncoprotein bcl-3 induces cyclin d1 to stimulate g(1) transition. Mol Cell Biol 2001; 21: 8428-36.
Geryk B, Macek M, Stolcova E, Luka J, Dibakova E. [late results following the operative treatment of congenital postero-lateral diaphragmatic hernia]. Zentralbl Chir 1984; 109: 1001-5.
Kong L, Zhao Q, Wang X, Zhu J, Hao D, Yang C. Angelica sinensis extract inhibits rankl-mediated osteoclastogenesis by down-regulated the expression of nfatc1 in mouse bone marrow cells. BMC Complement Altern Med 2014; 14: 481.
Delmore JE, Issa GC, Lemieux ME, et al. Bet bromodomain inhibition as a therapeutic strategy to target c-myc. Cell 2011; 146: 904-17.
Zuber J, Shi J, Wang E, et al. Rnai screen identifies brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011; 478: 524-8.
Goodridge HS, Simmons RM, Underhill DM. Dectin-1 stimulation by candida albicans yeast or zymosan triggers nfat activation in macrophages and dendritic cells. J Immunol 2007; 178: 3107-15.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [219 - 225]
Pages: 7
DOI: 10.2174/1574888X13666180723104340
Price: $65

Article Metrics

PDF: 51
HTML: 10