IKK promotes cytokine-induced and cancer-associated AMPK activity and attenuates phenformin-induced cell death in LKB1-deficient cells.
IKK promotes cytokine-induced and cancer-associated AMPK activity and attenuates phenformin-induced cell death in LKB1-deficient cells.
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DOI：
10.1126/scisignal.aan5850
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发表时间：
2018-07-10
影响因子：
7.3
通讯作者：
Baldwin AS
中科院分区：
文献类型：
--
作者：
Antonia RJ;Baldwin AS
5‘AMP激活的蛋白激酶(AMPK)是一种能量感受器，当其激活环中的Thr172被LKB1、CAMKK2或TAK1激活时被激活。与LKB1或CAMKK2对该位点的磷酸化相比，依赖于TAK1的Thr172的AMPK磷酸化的特征较差。Tak1的一个重要靶点是IκB激酶(IKK)，它控制转录因子NF-κB的激活。在这里，我们验证了IKK作用于Tak1下游通过磷酸化Thr172激活AMPK的假设。炎性细胞因子IL-1β或肿瘤坏死因子-α处理或TAK1过表达时，AMPK中Thr172的磷酸化需要IKK。此外，IKK独立于TAK1调节几种癌细胞的基础AMPK Thr172的磷酸化，这表明IKK的其他激活模式也可以刺激AMPK。我们发现IKK在Thr172直接磷酸化AMPK，而不依赖于肿瘤抑制因子LKB1或能量应激。因此，在LKB1缺失的细胞中，IKK抑制减少了AMPK Thr172的磷酸化，以响应线粒体抑制剂苯福明。这一反应导致了细胞凋亡的增强，并表明IKK抑制与苯福明联合应用可用于临床治疗LKB1缺陷的癌症患者。AMPK是一种炎性激活方式，其最著名的功能是作为能量状态的传感器，它是通过肿瘤抑制因子LKB1介导的磷酸化来激活的。Antonia和Baldwin描述了一种不同的AMPK激活途径，包括TAK1，一种与炎症途径相关的激酶。他们发现，这一过程需要TAK1靶标IKK对AMPK的磷酸化，并且它独立于LKB1发生，在某些细胞系中也独立于TAK1发生，这表明激活IKK的TAK1非依赖途径也可以刺激AMPK。将IKK抑制剂与抗癌药物苯福明相结合，提高了其杀死LKB1缺陷癌细胞的能力，突显了一种针对缺乏这种肿瘤抑制因子的癌症的新的潜在治疗方法。AMPK活性受IKK介导的癌细胞和炎性细胞因子下游磷酸化的刺激。
The 5’ AMP-activated protein kinase (AMPK) is an energy sensor that is activated upon phosphorylation of Thr172 in its activation loop by the kinases 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. Here, we tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172. IKK was required for phosphorylation of Thr172 in AMPK in response to treatment with the inflammatory cytokines IL-1β or TNF-α or upon TAK1 overexpression. Additionally, 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. An inflammatory way to activate AMPK In its best-known function as a sensor of energy status, the kinase AMPK is activated by phosphorylation mediated by the tumor suppressor LKB1. Antonia and Baldwin characterized a different pathway for AMPK activation involving TAK1, a kinase associated with inflammatory pathways. They found that this process required phosphorylation of AMPK by the TAK1 target IKK and that it occurred independently of LKB1 and, in certain cell lines, independently of TAK1 as well, indicating that TAK1-independent pathways that activate IKK could also stimulate AMPK. Combining an IKK inhibitor with the cancer drug phenformin improved its ability to kill LKB1-deficient cancer cells, highlighting a new potential treatment for cancers lacking this tumor suppressor. AMPK activity is stimulated by IKK-mediated phosphorylation in cancer cells and downstream of inflammatory cytokines.
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影响因子：
4.1
作者：
Johnsen, Elin;Wilson, Steven Ray;Lundanes, Elsa
通讯作者：
Lundanes, Elsa
影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
29
作者：
Gowans GJ;Hawley SA;Ross FA;Hardie DG
通讯作者：
Hardie DG
AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
21.3
作者：
通讯作者：
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