p53 and the Carcinogenicity of Chronic Inflammation
p53 and the Carcinogenicity of Chronic Inflammation
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DOI：
10.1101/cshperspect.a026161
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发表时间：
2016-11-01
影响因子：
5.4
通讯作者：
Komarova, Elena A.
中科院分区：
文献类型：
--
作者：
Gudkov, Andrei V.;Komarova, Elena A.
慢性炎症是导致癌症的主要因素。炎症驱动NF-kappa B通路的组成性激活通常在癌症中观察到，或在正常组织中由于持续感染或内源性组织刺激因子（包括衰老细胞随年龄积累的分泌产物）而发展，显著抑制p53功能。反过来，p53作为炎症的抑制因子，帮助将其保持在安全范围内。p53和NF-kappa B之间的拮抗关系受多种机制控制，反映了这两种转录因子分别驱动的机体对内源性和外源性细胞应激反应的基本差异。这为开发药物提供了一个机会，通过靶向相反的途径来治疗与p53或NF-kappa B不适当活性相关的疾病。这类药物的几种候选药物目前正在临床试验中。这些包括抗癌小分子，能够同时抑制p53和激活NF-kappa B和NF-kappa B激活生物制剂，这些生物制剂可以抵消p53介导的与系统性基因毒性应激相关的病理，如急性辐射综合征和癌症治疗的副作用。
Chronic inflammation is a major cancer predisposition factor. Constitutive activation of the inflammation-driving NF-kappa B pathway commonly observed in cancer or developed in normal tissues because of persistent infections or endogenous tissue irritating factors, including products of secretion by senescent cells accumulating with age, markedly represses p53 functions. In its turn, p53 acts as a suppressor of inflammation helping to keep it within safe limits. The antagonistic relationship between p53 and NF-kappa B is controlled by multiple mechanisms and reflects cardinal differences in organismal responses to intrinsic and extrinsic cell stresses driven by these two transcription factors, respectively. This provides an opportunity for developing drugs to treat diseases associated with inappropriate activity of either p53 or NF-kappa B through targeting the opposing pathway. Several drug candidates of this kind are currently in clinical testing. These include anticancer small molecules capable of simultaneous suppression of p53 and activation of NF-kappa B and NF-kappa B-activating biologics that counteract p53-mediated pathologies associated with systemic genotoxic stresses such as acute radiation syndrome and side effects of cancer treatment.