The 5' AMP-activated protein kinase (AMPK) is an energy sensor that is activated upon phosphorylation of Thr172 in its activation loop by the kinase LKB1, CAMKK2, or TAK1. TAK1-dependent AMPK phosphorylation of Thr172 is less well characterized than phosphorylation of this site by LKB1 or CAMKK2. An important target of TAK1 is IκB kinase (IKK), which controls the activation of the transcription factor NF-κB. We tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172 IKK was required for the phosphorylation of Thr172 in AMPK in response to treatment with the inflammatory cytokine IL-1β or TNF-α or upon TAK1 overexpression. In addition, IKK regulated basal AMPK Thr172 phosphorylation in several cancer cell types independently of TAK1, indicating that other modes of IKK activation could stimulate AMPK. We found that IKK directly phosphorylated AMPK at Thr172 independently of the tumor suppressor LKB1 or energy stress. Accordingly, in LKB1-deficient cells, IKK inhibition reduced AMPK Thr172 phosphorylation in response to the mitochondrial inhibitor phenformin. This response led to enhanced apoptosis and suggests that IKK inhibition in combination with phenformin could be used clinically to treat patients with LKB1-deficient cancers.

中文翻译：

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IKK促进LKB1缺陷细胞中细胞因子诱导的和癌症相关的AMPK活性，并减弱苯乙双胍诱导的细胞死亡。

5'AMP激活的蛋白激酶（AMPK）是一种能量传感器，在其激活环中的Thr172磷酸化后被激酶LKB1，CAMKK2或TAK1激活。Thr172的TAK1依赖的AMPK磷酸化的特征不如LKB1或CAMKK2磷酸化该位点。TAK1的重要靶标是IκB激酶（IKK），它可控制转录因子NF-κB的激活。我们测试了以下假设：IKK通过使Thr172磷酸化而作用于TAK1下游以激活AMPK。响应炎症性细胞因子IL-1β或TNF-α的治疗或TAK1过表达，IKK对于AMPK中Thr172的磷酸化是必需的。此外，IKK独立于TAK1调节几种癌细胞类型中的基础AMPK Thr172磷酸化，表明IKK激活的其他方式可以刺激AMPK。我们发现，IKK直接在Thr172处使AMPK磷酸化，而与肿瘤抑制因子LKB1或能量应激无关。因此，在LKB1缺陷的细胞中，IKK抑制作用会响应线粒体抑制剂苯乙双胍而降低AMPK Thr172的磷酸化。该反应导致细胞凋亡增强，提示IKK抑制与苯乙双胍联用可在临床上用于治疗LKB1缺陷型癌症患者。