Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death.
Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death.
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DOI：
10.1038/msb.2012.20
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发表时间：
2012-06-26
影响因子：
9.9
通讯作者：
Graeber, Thomas G.
中科院分区：
文献类型：
--
作者：
Graham, Nicholas A.;Tahmasian, Martik;Kohli, Bitika;Komisopoulou, Evangelia;Zhu, Maggie;Vivanco, Igor;Teitell, Michael A.;Wu, Hong;Ribas, Antoni;Lo, Roger S.;Mellinghoff, Ingo K.;Mischel, Paul S.;Graeber, Thomas G.
癌症的代谢改变可以使细胞依赖于代谢底物的可用性来维持生存。研究细胞死亡的信号机制依赖于葡萄糖的生存，我们证明，葡萄糖戒断迅速诱导超生理水平的磷酸酪氨酸信号，即使在细胞表达组成型活性酪氨酸激酶。使用无偏质谱为基础的磷酸蛋白质组学，我们表明，葡萄糖戒断启动一个独特的签名磷酸酪氨酸激活与局灶性粘连。基于这一观察结果，我们证明葡萄糖戒断激活了一个正反馈回路，涉及NADPH氧化酶和线粒体产生活性氧（ROS），通过氧化抑制蛋白酪氨酸磷酸酶，并增加酪氨酸激酶信号传导。在依赖于葡萄糖存活的细胞中，葡萄糖戒断诱导的ROS产生和酪氨酸激酶信号传导协同作用以放大ROS水平，最终导致ROS介导的细胞死亡。总之，这些发现说明了在维持癌细胞稳态中代谢和信号传导之间的系统水平串扰。
The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra-physiological levels of phospho-tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry-based phospho-proteomics, we show that glucose withdrawal initiates a unique signature of phospho-tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal-induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS-mediated cell death. Taken together, these findings illustrate the systems-level cross-talk between metabolism and signaling in the maintenance of cancer cell homeostasis.
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DOI：
10.1073/pnas.0804336105
发表时间：
2008-07-22
影响因子：
11.1
作者：
Boivin, Benoit;Zhangt, Sheng;Tonks, Nicholas K.
通讯作者：
Tonks, Nicholas K.
影响因子：
8
作者：
Buzzai, M;Bauer, DE;Thompson, CB
通讯作者：
Thompson, CB
影响因子：
11.2
作者：
Andringa, KK;Coleman, NC;Spitz, DR
通讯作者：
Spitz, DR
禁食周期阻碍肿瘤的生长，并使一系列癌细胞类型对化学疗法敏感。
影响因子：
17.1
作者：
Lee C;Raffaghello L;Brandhorst S;Safdie FM;Bianchi G;Martin-Montalvo A;Pistoia V;Wei M;Hwang S;Merlino A;Emionite L;de Cabo R;Longo VD
通讯作者：
Longo VD
影响因子：
7.3
作者：
Kwon J;Shatynski KE;Chen H;Morand S;de Deken X;Miot F;Leto TL;Williams MS
通讯作者：
Williams MS