NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress.
NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress.
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DOI：
10.1038/s41419-020-03383-z
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发表时间：
2021-03-15
影响因子：
9
通讯作者：
Sitcheran R
中科院分区：
文献类型：
--
作者：
Kamradt ML;Jung JU;Pflug KM;Lee DW;Fanniel V;Sitcheran R
包括多形胶质母细胞瘤（GBM）在内的癌症，在不同的肿瘤微环境中，通过代谢途径的协调重编程来控制糖酵解和氧化磷酸化（OXPHOS），从而促进肿瘤生长。对微环境中有限的营养物质的适应与线粒体形态和生物能量能力的重塑有关。我们最近发现NF-κ b诱导激酶（NIK）调节线粒体形态，促进GBM细胞侵袭。在这里，我们发现NIK被招募到分裂线粒体的外膜与主裂变调节因子，动力蛋白相关蛋白1 （DRP1）。此外，葡萄糖剥夺介导的向OXPHOS的代谢转变增加了NIK和DRP1的裂变和线粒体定位。NIK缺乏导致线粒体呼吸、ATP产生和备用呼吸能力（SRC）减少，这是线粒体健康的关键指标。虽然高糖条件下OXPHOS需要IκB激酶α和β (IKKα/β)和NIK，但在葡萄糖剥夺条件下，增加SRC只需要NIK。与NIK在调节代谢中的ikk独立作用一致，我们表明NIK在体外和体内磷酸化DRP1-S616。值得注意的是，组成型活性DRP1-S616E突变体在不诱导IKK的情况下挽救了NIK - / -细胞的氧化代谢、侵袭性和致瘤潜力。因此，我们确定NIK是独立于IKK的生物能量应激反应促进GBM细胞发病的关键。我们的数据表明，靶向NIK可能用于利用代谢脆弱性和改善GBM的治疗策略。
Cancers, including glioblastoma multiforme (GBM), undergo coordinated reprogramming of metabolic pathways that control glycolysis and oxidative phosphorylation (OXPHOS) to promote tumor growth in diverse tumor microenvironments. Adaptation to limited nutrient availability in the microenvironment is associated with remodeling of mitochondrial morphology and bioenergetic capacity. We recently demonstrated that NF-κB-inducing kinase (NIK) regulates mitochondrial morphology to promote GBM cell invasion. Here, we show that NIK is recruited to the outer membrane of dividing mitochondria with the master fission regulator, Dynamin-related protein1 (DRP1). Moreover, glucose deprivation-mediated metabolic shift to OXPHOS increases fission and mitochondrial localization of both NIK and DRP1. NIK deficiency results in decreased mitochondrial respiration, ATP production, and spare respiratory capacity (SRC), a critical measure of mitochondrial fitness. Although IκB kinase α and β (IKKα/β) and NIK are required for OXPHOS in high glucose media, only NIK is required to increase SRC under glucose deprivation. Consistent with an IKK-independent role for NIK in regulating metabolism, we show that NIK phosphorylates DRP1-S616 in vitro and in vivo. Notably, a constitutively active DRP1-S616E mutant rescues oxidative metabolism, invasiveness, and tumorigenic potential in NIK−/− cells without inducing IKK. Thus, we establish that NIK is critical for bioenergetic stress responses to promote GBM cell pathogenesis independently of IKK. Our data suggest that targeting NIK may be used to exploit metabolic vulnerabilities and improve therapeutic strategies for GBM.
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DOI：
10.1083/jcb.201511036
发表时间：
2016-02-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mishra P;Chan DC
通讯作者：
Chan DC
影响因子：
29
作者：
Arroyo JD;Jourdain AA;Calvo SE;Ballarano CA;Doench JG;Root DE;Mootha VK
通讯作者：
Mootha VK
影响因子：
29
作者：
Marin-Valencia I;Yang C;Mashimo T;Cho S;Baek H;Yang XL;Rajagopalan KN;Maddie M;Vemireddy V;Zhao Z;Cai L;Good L;Tu BP;Hatanpaa KJ;Mickey BE;Matés JM;Pascual JM;Maher EA;Malloy CR;Deberardinis RJ;Bachoo RM
通讯作者：
Bachoo RM
影响因子：
8
作者：
Li, J.;Huang, Q.;Xing, J.
通讯作者：
Xing, J.
影响因子：
5.2
作者：
Chang CR;Blackstone C
通讯作者：
Blackstone C