Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Oncogene. 2011 Apr 7;30(14):1615-30. doi: 10.1038/onc.2010.566. Epub 2010 Dec 20.
Activation of nuclear factor (NF)-κB, 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-κB is constitutively active in most tumor cells, and its suppression inhibits the growth of tumor cells, leading to the concept of 'NF-κB addiction' in cancer cells. Why NF-κB is constitutively and persistently active in cancer cells is not fully understood, but multiple mechanisms have been delineated including agents that activate NF-κB (such as viruses, viral proteins, bacteria and cytokines), signaling intermediates (such as mutant receptors, overexpression of kinases, mutant oncoproteins, degradation of IκBα, histone deacetylase, overexpression of transglutaminase and iNOS) and cross talk between NF-κB and other transcription factors (such as STAT3, HIF-1α, AP1, SP, p53, PPARγ, β-catenin, AR, GR and ER). As NF-κB is 'pre-active' in cancer cells through unrelated mechanisms, classic inhibitors of NF-κB (for example, bortezomib) are unlikely to mediate their anticancer effects through suppression of NF-κB. This review discusses multiple mechanisms of NF-κB activation and their regulation by multitargeted agents in contrast to monotargeted agents, thus 'one size does not fit all' cancers.
核因子（NF）-κB 的激活是研究最多的转录因子之一，已发现其控制癌症中的多种细胞过程，包括炎症、转化、增殖、血管生成、侵袭、转移、化疗耐药和放射耐药。NF-κB 在大多数肿瘤细胞中持续激活，其抑制可抑制肿瘤细胞的生长，导致癌细胞的“NF-κB 成瘾”概念。为什么 NF-κB 在癌细胞中持续和持久地激活尚未完全理解，但已阐明多种机制，包括激活 NF-κB 的试剂（如病毒、病毒蛋白、细菌和细胞因子）、信号中间物（如突变受体、激酶过表达、突变癌蛋白、IκBα降解、组蛋白去乙酰化酶、转谷氨酰胺酶和 iNOS 过表达）以及 NF-κB 与其他转录因子（如 STAT3、HIF-1α、AP1、SP、p53、PPARγ、β-连环蛋白、AR、GR 和 ER）之间的串扰。由于 NF-κB 通过无关机制在癌细胞中处于“预激活”状态，因此经典的 NF-κB 抑制剂（例如硼替佐米）不太可能通过抑制 NF-κB 发挥其抗癌作用。这篇综述讨论了 NF-κB 激活的多种机制及其与多靶点药物的调节与单靶点药物的调节不同，因此“一刀切”并不适用于所有癌症。
