Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human cancer, and antioxidant defenses are implicated in resistance to chemotherapy and radiotherapy. Targeted suppression of antioxidant defenses could thus broadly improve therapeutic outcomes. Here, we identify the AMPK-related kinase NUAK1 as a key component of the antioxidant stress response pathway and reveal a specific requirement for this role of NUAK1 in colorectal cancer. We show that NUAK1 is activated by oxidative stress and that this activation is required to facilitate nuclear import of the antioxidant master regulator NRF2: Activation of NUAK1 coordinates PP1β inhibition with AKT activation in order to suppress GSK3β-dependent inhibition of NRF2 nuclear import. Deletion of NUAK1 suppresses formation of colorectal tumors, whereas acute depletion of NUAK1 induces regression of preexisting autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.

Significance: This work identifies NUAK1 as a key facilitator of the adaptive antioxidant response that is associated with aggressive disease and worse outcome in human colorectal cancer. Our data suggest that transient NUAK1 inhibition may provide a safe and effective means for treatment of human colorectal cancer via disruption of intrinsic antioxidant defenses. Cancer Discov; 8(5); 632–47. ©2018 AACR.

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利用氧化应激最近已成为治疗人类癌症的一种可行策略，抗氧化防御与化学疗法和放射疗法的抗性有关。因此，有针对性地抑制抗氧化剂防御可以广泛改善治疗效果。在这里，我们确定与AMPK相关的激酶NUAK1是抗氧化应激反应途径的关键组成部分，并揭示了NUAK1在结肠直肠癌中的这一作用的特殊要求。我们显示NUAK1被氧化应激激活，并且需要这种激活来促进抗氧化剂主调节剂NRF2的核导入：NUAK1的激活与AKT激活协调PP1β抑制，从而抑制GSK3β依赖性的NRF2核导入的抑制。删除NUAK1可抑制结直肠肿瘤的形成，而NUAK1的急性耗竭则可导致先前存在的自发性肿瘤消退。重要的是，NUAK1在人大肠癌中的表达升高与更具侵略性的疾病和降低的总生存率有关。

启示：这项工作确定了NUAK1是与人类大肠癌的侵袭性疾病和较差结果相关的适应性抗氧化剂反应的关键促进剂。我们的数据表明，短暂的NUAK1抑制作用可能会通过破坏内在的抗氧化剂防御提供一种安全有效的方法来治疗人类大肠癌。巨蟹座Discov; 8（5）；632–47。©2018 AACR。

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