Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress.
Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress.
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DOI：
10.1158/2159-8290.cd-17-0533
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发表时间：
2018-05
期刊：
影响因子：
28.2
通讯作者：
Murphy DJ
中科院分区：
文献类型：
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作者：
Port J;Muthalagu N;Raja M;Ceteci F;Monteverde T;Kruspig B;Hedley A;Kalna G;Lilla S;Neilson L;Brucoli M;Gyuraszova K;Tait-Mulder J;Mezna M;Svambaryte S;Bryson A;Sumpton D;McVie A;Nixon C;Drysdale M;Esumi H;Murray GI;Sansom OJ;Zanivan SR;Murphy DJ
最近，利用氧化应激已成为治疗人类癌症的一种可行策略，抗氧化剂防御与化疗和放射治疗的耐药性有关。因此，靶向抑制抗氧化防御可以广泛改善治疗结果。在这里，我们确定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在结直肠癌中这一作用的特殊要求。我们证明了NUAK1是由氧化应激激活的，这种激活是促进抗氧化剂主调控因子NRF2核导入所必需的：NUAK1的激活协调了PP1AKT的β抑制和AKT激活，以抑制GSK3β依赖的对NRF2核导入的抑制。NUAK1的缺失抑制了结直肠肿瘤的形成，而NUAK1的急性缺失则导致原有的原发肿瘤的消退。重要的是，NUAK1在人类结直肠癌中的高表达与更具侵袭性的疾病和总体生存率降低有关。
Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human Cancer and anti-oxidant defences are implicated in resistance to chemo- and radiotherapy. Targeted suppression of anti-oxidant defences could thus broadly improve therapeutic outcomes. Here we identify the AMPK-related kinase NUAK1 as a key component of the anti-oxidant 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 anti-oxidant 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, while acute depletion of NUAK1 induces regression of pre-existing autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.