Journal
ONCOGENE
Volume 30, Issue 14, Pages 1615-1630Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.566
Keywords
NF-kappa B; constitutive activation; cancer; inflammation; multitargeted therapy
Funding
- Clayton Foundation for Research
- National Institutes of Health [CA-16 672, NIH CA-124787-01A2]
- Center for Targeted Therapy of MD Anderson Cancer Center
- University of Delhi, Department of Science & Technology, India [Dean(R)/2010/1142]
- MD Anderson Cancer Center
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Activation of nuclear factor (NF)-kappa B, one of the most investigated transcription factors, has been found to control multiple cellular processes in cancer including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance and radioresistance. NF-kappa B is constitutively active in most tumor cells, and its suppression inhibits the growth of tumor cells, leading to the concept of 'NF-kappa B addiction' in cancer cells. Why NF-kappa B is constitutively and persistently active in cancer cells is not fully understood, but multiple mechanisms have been delineated including agents that activate NF-kappa B (such as viruses, viral proteins, bacteria and cytokines), signaling intermediates (such as mutant receptors, overexpression of kinases, mutant oncoproteins, degradation of I kappa B alpha, histone deacetylase, overexpression of transglutaminase and iNOS) and cross talk between NF-kappa B and other transcription factors (such as STAT3, HIF-1 alpha, AP1, SP, p53, PPAR gamma, beta-catenin, AR, GR and ER). As NF-kappa B is 'pre-active' in cancer cells through unrelated mechanisms, classic inhibitors of NF-kappa B (for example, bortezomib) are unlikely to mediate their anticancer effects through suppression of NF-kappa B. This review discusses multiple mechanisms of NF-kappa B activation and their regulation by multitargeted agents in contrast to monotargeted agents, thus 'one size does not fit all' cancers. Oncogene (2011) 30, 1615-1630; doi:10.1038/onc.2010.566; published online 20 December 2010
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