Ravi Rajani, Bedi Atul
The Bunting Family-The Family of Jacob and Hilda Blaustein Building for Cancer Research, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231-1000, USA.
Drug Resist Updat. 2004 Feb;7(1):53-67. doi: 10.1016/j.drup.2004.01.003.
The nuclear factor of kappaB (NF-kappaB) family of heterodimeric transcription factors plays an instrumental role in immune, inflammatory, and stress responses. NF-kappaB induces the expression of diverse target genes that promote cell cycle progression, regulate apoptosis, and facilitate cell adhesion, angiogenesis, and metastasis. Given the ability of NF-kappaB to influence these cardinal features of neoplastic transformation, it is no surprise that tumor cells of almost every tissue type acquire the ability to constitutively activate NF-kappaB via a host of diverse genetic alterations and viral proteins. The activation of NF-kappaB not only enables malignant transformation and tumor progression, but also provides a mechanism by which tumor cells escape immune surveillance and resist therapy. NF-kappaB may be inhibited by targeting either the apical signaling proteins responsible for its activation in specific types of cancer, the downstream kinases (IkappaB kinase and casein kinase 2) at which NF-kappaB-activating signaling pathways converge, the proteasome-mediated degradation of the inhibitor of kappaB (IkappaB) proteins, or the transcriptional activity of Rel proteins. Since NF-kappaB inhibitors can sensitize tumor cells to apoptosis signaling pathways activated by death receptors, interferons, and immune effector cells, they hold enormous promise for the development of effective combinatorial regimens against a wide spectrum of hematologic and epithelial malignancies.
κB核因子（NF-κB）家族的异二聚体转录因子在免疫、炎症和应激反应中发挥着重要作用。NF-κB诱导多种靶基因的表达，这些基因促进细胞周期进程、调节细胞凋亡，并促进细胞黏附、血管生成和转移。鉴于NF-κB能够影响肿瘤转化的这些主要特征，几乎每种组织类型的肿瘤细胞通过多种不同的基因改变和病毒蛋白获得组成性激活NF-κB的能力也就不足为奇了。NF-κB的激活不仅能使恶性转化和肿瘤进展，还提供了一种肿瘤细胞逃避免疫监视和抵抗治疗的机制。可以通过靶向负责其在特定类型癌症中激活的顶端信号蛋白、NF-κB激活信号通路汇聚的下游激酶（κB激酶和酪蛋白激酶2）、蛋白酶体介导的κB抑制蛋白（IkappaB）的降解或Rel蛋白的转录活性来抑制NF-κB。由于NF-κB抑制剂可使肿瘤细胞对死亡受体、干扰素和免疫效应细胞激活的凋亡信号通路敏感，它们在开发针对广泛血液系统和上皮恶性肿瘤的有效联合治疗方案方面具有巨大潜力。
