IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways.
IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways.
复制标题
IKKα 失活通过破坏主要氧化还原调节途径促进 Kras 引发的肺腺癌发展
DOI：
10.1073/pnas.1717520115
复制
发表时间：
2018-01-23
影响因子：
11.1
通讯作者：
Hu Y
中科院分区：
文献类型：
--
作者：
Song NY;Zhu F;Wang Z;Willette-Brown J;Xi S;Sun Z;Su L;Wu X;Ma B;Nussinov R;Xia X;Schrump DS;Johnson PF;Karin M;Hu Y
意义 活性氧（ROS）可以促进肿瘤发生或杀死癌细胞。不同的癌症相关基因改变如何调节 ROS 平衡和结果对于设计合理的癌症治疗非常重要，其中许多治疗会影响 ROS 代谢和传感。 Kras 激活会诱导 ROS 防御系统和细胞衰老，从而抵消其致癌活性。 KRAS 激活突变伴随着 IKKα 缺失突变，导致 NOX2 升高，但 NRF2 ROS 防御系统表达降低。因此，IKKα 消融将 Kras 诱导的 ROS 的抗肿瘤作用转变为促肿瘤作用，从而增强 Kras 诱导的肺腺癌 (ADC) 进展。恢复 IKKα 活性或抑制其丢失时激活的通路可能为 ADC 治疗提供新的机会。肺腺癌（ADC）和鳞状细胞癌（SCC）是两种不同且主要的人类肺癌类型。 IκB 激酶 α (IKKα) 已被证明可以抑制肺 SCC 的发展，但其在 ADC 中的作用尚不清楚。我们在人肺 ADC 的编码 IKKα 的 CHUK 基因座中发现了失活突变和同源或半合子缺失。 CHUK 缺失显着缩短了携带 KRAS 突变的肺部 ADC 患者的生存时间。在小鼠中，肺特异性 Ikkα 消融 (IkkαΔLu) 诱导自发 ADC 并促进 KrasG12D 启动的 ADC 发育，同时伴有细胞增殖增加、细胞衰老减少和活性氧 (ROS) 积累。 IKKα 缺失上调 NOX2 并下调 NRF2，导致 ROS 积累并阻断细胞衰老诱导，共同加速 ADC 的发育。 NADPH 氧化酶或 ROS 的药理学抑制会损害 IkkαΔLu 小鼠中 KrasG12D 介导的 ADC 发育。因此，IKKα 通过控制氧化还原调节途径来调节肺 ADC 的发育。这项研究表明，IKKα 通过调节肿瘤细胞相关 ROS 代谢的独特机制，在人和小鼠中充当肺 ADC 的抑制剂。
Significance Reactive oxygen species (ROS) can promote tumorigenesis or kill cancer cells. How different cancer-associated genetic alterations regulate ROS balance and outcome is of great importance for the design of rational cancer treatments, many of which affect ROS metabolism and sensing. Kras activation induces a ROS defense system and cell senescence, which counteract its oncogenic activity. KRAS-activating mutations are accompanied by IKKα loss mutations that result in elevated NOX2 but decreased expression of the NRF2 ROS defense system. Thus, IKKα ablation turns the antitumorigenic effect of Kras-induced ROS to a protumorigenic effect that enhances Kras-induced progression of lung adenocarcinoma (ADC). Restoration of IKKα activity or inhibition of the pathways activated on its loss may offer new opportunities for ADC treatment. Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkα ablation (IkkαΔLu) induces spontaneous ADCs and promotes KrasG12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs KrasG12D-mediated ADC development in IkkαΔLu mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism.
登录
查看更多内容
影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
5.3
作者：
Coant, Nicolas;Ben Mkaddem, Sanae;Ogier-Denis, Eric
通讯作者：
Ogier-Denis, Eric
影响因子：
4.8
作者：
Khan, Elaine M.;Heidinger, Jill M.;Goldkorn, Tzipora
通讯作者：
Goldkorn, Tzipora
影响因子：
9.2
作者：
Lehnertz, B;Ueda, Y;Peters, AHFM
通讯作者：
Peters, AHFM
影响因子：
64.5
作者：
Chio IIC;Jafarnejad SM;Ponz-Sarvise M;Park Y;Rivera K;Palm W;Wilson J;Sangar V;Hao Y;Öhlund D;Wright K;Filippini D;Lee EJ;Da Silva B;Schoepfer C;Wilkinson JE;Buscaglia JM;DeNicola GM;Tiriac H;Hammell M;Crawford HC;Schmidt EE;Thompson CB;Pappin DJ;Sonenberg N;Tuveson DA
通讯作者：
Tuveson DA