IKKβ activates p53 to promote cancer cell adaptation to glutamine deprivation.
IKKβ activates p53 to promote cancer cell adaptation to glutamine deprivation.
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DOI：
10.1038/s41389-018-0104-0
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发表时间：
2018-11-26
期刊：
影响因子：
6.2
通讯作者：
Kong M
中科院分区：
文献类型：
--
作者：
Ishak Gabra MB;Yang Y;Lowman XH;Reid MA;Tran TQ;Kong M
癌症的标志之一是能够重新编程细胞代谢，以增加对葡萄糖和谷氨酰胺等必要营养素的摄取。在癌基因的驱动下，癌细胞增加了谷氨酰胺的摄取，以支持其高度增殖的性质。然而，随着癌细胞继续复制和生长，它们失去了进入血管组织的途径，耗尽了局部的营养和氧气供应。我们以前表明，许多肿瘤细胞在体内低谷氨酰胺微环境中生长，但它们如何适应这种代谢应激的机制仍不完全清楚。在这里，我们报告说，Iκ B-激酶β（IKKβ）是促进生存所必需的，其激活伴随着代谢传感器p53的磷酸化，以响应谷氨酰胺剥夺。IKKβ的敲低降低了野生型和突变型p53磷酸化水平及其转录活性，表明IKKβ和p53在介导对谷氨酰胺戒断反应的癌细胞存活中存在新的关系。磷酸肽质谱分析进一步揭示，IKKβ磷酸化丝氨酸392上的p53，以促进其在谷氨酰胺剥夺后的激活，独立于NF-κB途径。这项研究的结果提供了对癌细胞中代谢重编程的深入了解，该代谢重编程依赖于先前未识别的IKKβ-p53信号传导轴，以响应谷氨酰胺耗尽。更重要的是，这项研究强调了一种新的癌症治疗策略，并推进了我们对可能导致对当前谷氨酰胺靶向治疗耐药的适应性机制的理解。
One of the hallmarks of cancer is the ability to reprogram cellular metabolism to increase the uptake of necessary nutrients such as glucose and glutamine. Driven by oncogenes, cancer cells have increased glutamine uptake to support their highly proliferative nature. However, as cancer cells continue to replicate and grow, they lose access to vascular tissues and deplete local supply of nutrients and oxygen. We previously showed that many tumor cells situate in a low glutamine microenvironment in vivo, yet the mechanisms of how they are able to adapt to this metabolic stress are still not fully understood. Here, we report that IκB-kinase β (IKKβ) is needed to promote survival and its activation is accompanied by phosphorylation of the metabolic sensor, p53, in response to glutamine deprivation. Knockdown of IKKβ decreases the level of wild-type and mutant p53 phosphorylation and its transcriptional activity, indicating a novel relationship between IKKβ and p53 in mediating cancer cell survival in response to glutamine withdrawal. Phosphopeptide mass spectrometry analysis further reveals that IKKβ phosphorylates p53 on Ser392 to facilitate its activation upon glutamine deprivation, independent of the NF-κB pathway. The results of this study offer an insight into the metabolic reprogramming in cancer cells that is dependent on a previously unidentified IKKβ–p53 signaling axis in response to glutamine depletion. More importantly, this study highlights a new therapeutic strategy for cancer treatment and advances our understanding of adaptive mechanisms that could lead to resistance to current glutamine targeting therapies.
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影响因子：
64.5
作者：
Liu J;Ibi D;Taniguchi K;Lee J;Herrema H;Akosman B;Mucka P;Salazar Hernandez MA;Uyar MF;Park SW;Karin M;Ozcan U
通讯作者：
Ozcan U
影响因子：
37.3
作者：
Denkert C;Budczies J;Weichert W;Wohlgemuth G;Scholz M;Kind T;Niesporek S;Noske A;Buckendahl A;Dietel M;Fiehn O
通讯作者：
Fiehn O
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