IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3.
IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3.
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IKKβ通过磷酸化和抑制PFKFB3促进了对谷氨酰胺剥夺的代谢适应。
DOI：
10.1101/gad.287235.116
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发表时间：
2016-08-15
影响因子：
10.5
通讯作者：
Kong M
中科院分区：
文献类型：
--
作者：
Reid MA;Lowman XH;Pan M;Tran TQ;Warmoes MO;Ishak Gabra MB;Yang Y;Locasale JW;Kong M
在这项研究中，Reid等人研究了癌细胞如何适应低谷氨酰胺条件，这是癌细胞增殖和生存所必需的。他们发现IKKβ直接与PFKFB3相互作用，并在谷氨酰胺剥夺时磷酸化其Ser269位点，从而抑制其活性，从而在谷氨酰胺水平低时下调有氧糖酵解，从而为癌细胞适应提供新的见解。谷氨酰胺是癌细胞生存和增殖所必需的营养物质。谷氨酰胺的增强利用经常耗尽其局部供应，然而癌细胞如何适应低谷氨酰胺条件在很大程度上是未知的。在这里，我们报道了ikb激酶β (IKKβ)在谷氨酰胺剥夺时被激活，并且是独立于NF-κB转录的细胞存活所必需的。我们证明IKKβ直接与6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶异构体3 （PFKFB3）相互作用并使其磷酸化，这是谷氨酰胺剥夺时有氧糖酵解的主要驱动因素，在Ser269位点抑制其活性，从而在谷氨酰胺水平低时下调有氧糖酵解。因此，由于缺乏对PFKFB3的抑制，ikk β缺陷细胞表现出有氧糖酵解和乳酸生成的升高，导致葡萄糖碳减少，有助于三羧酸（TCA）循环中间体和戊糖磷酸途径，这导致对TCA循环中间体和活性氧抑制的谷氨酰胺依赖性增加。因此，在体内和体外，IKKβ和谷氨酰胺代谢的共同抑制导致癌细胞的显著协同杀伤。总之，我们的研究结果揭示了IKKβ在调节糖酵解、感知低谷氨酰胺诱导的代谢应激和促进细胞对营养可用性的适应方面的作用。
In this study, Reid et al. investigate how cancer cells adapt to low glutamine conditions, which is needed for cancer cell proliferation and survival. They show that IKKβ directly interacts with and phosphorylates PFKFB3, a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low and thus providing new insights into cancer cell adaptation. Glutamine is an essential nutrient for cancer cell survival and proliferation. Enhanced utilization of glutamine often depletes its local supply, yet how cancer cells adapt to low glutamine conditions is largely unknown. Here, we report that IκB kinase β (IKKβ) is activated upon glutamine deprivation and is required for cell survival independently of NF-κB transcription. We demonstrate that IKKβ directly interacts with and phosphorylates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform 3 (PFKFB3), a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low. Thus, due to lack of inhibition of PFKFB3, IKKβ-deficient cells exhibit elevated aerobic glycolysis and lactate production, leading to less glucose carbons contributing to tricarboxylic acid (TCA) cycle intermediates and the pentose phosphate pathway, which results in increased glutamine dependence for both TCA cycle intermediates and reactive oxygen species suppression. Therefore, coinhibition of IKKβ and glutamine metabolism results in dramatic synergistic killing of cancer cells both in vitro and in vivo. In all, our results uncover a previously unidentified role of IKKβ in regulating glycolysis, sensing low-glutamine-induced metabolic stress, and promoting cellular adaptation to nutrient availability.
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影响因子：
14.9
作者：
Baspinar A;Cukuroglu E;Nussinov R;Keskin O;Gursoy A
通讯作者：
Gursoy A
影响因子：
16
作者：
Comb, William C.;Hutti, Jessica E.;Baldwin, Albert S.
通讯作者：
Baldwin, Albert S.
影响因子：
21.3
作者：
Kawauchi, Keiko;Araki, Keigo;Tanaka, Nobuyuki
通讯作者：
Tanaka, Nobuyuki
影响因子：
11.2
作者：
Kamphorst JJ;Nofal M;Commisso C;Hackett SR;Lu W;Grabocka E;Vander Heiden MG;Miller G;Drebin JA;Bar-Sagi D;Thompson CB;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
21.3
作者：
Boroughs LK;DeBerardinis RJ
通讯作者：
DeBerardinis RJ