ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis
ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis
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DOI：
10.1038/emboj.2009.32
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发表时间：
2009-04-08
期刊：
影响因子：
11.4
通讯作者：
Ichijo, Hidenori
中科院分区：
文献类型：
--
作者：
Iriyama, Takayuki;Takeda, Kohsuke;Ichijo, Hidenori
细胞凋亡和炎症通常对肿瘤发生产生相反的影响：细胞凋亡是肿瘤发生的屏障，而炎症则促进肿瘤发生。尽管这两种事件都是由各种常见的应激源诱导的，但对于在肿瘤发生中调节这些事件的应激诱导的信号通路知之甚少。在这里，我们发现应激激活的 MAP3K、ASK1 和 ASK2 参与细胞对活性氧等各种应激源的反应，差异性地调节肿瘤发生的启动和促进。 ASK2 与 ASK1 协同作用，通过在上皮细胞中发挥促凋亡活性，发挥肿瘤抑制因子的作用，这与人类癌细胞和组织中 ASK2 表达的减少一致。相反，炎症细胞中 ASK1 依赖性细胞因子的产生促进了肿瘤发生。我们的研究结果表明，ASK1 和 ASK2 通过差异调节细胞凋亡和炎症而在肿瘤发生中发挥重要作用。
Apoptosis and inflammation generally exert opposite effects on tumorigenesis: apoptosis serves as a barrier to tumour initiation, whereas inflammation promotes tumorigenesis. Although both events are induced by various common stressors, relatively little is known about the stress-induced signalling pathways regulating these events in tumorigenesis. Here, we show that stress-activated MAP3Ks, ASK1 and ASK2, which are involved in cellular responses to various stressors such as reactive oxygen species, differentially regulate the initiation and promotion of tumorigenesis. ASK2 in cooperation with ASK1 functioned as a tumour suppressor by exerting proapoptotic activity in epithelial cells, which was consistent with the reduction in ASK2 expression in human cancer cells and tissues. In contrast, ASK1-dependent cytokine production in inflammatory cells promoted tumorigenesis. Our findings suggest that ASK1 and ASK2 are critically involved in tumorigenesis by differentially regulating apoptosis and inflammation.