Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.
Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.
复制标题
转化和HIF-1α依赖性代谢重编程基础代谢可塑性以及对激酶抑制剂和BIGUANIDE的反应。
DOI：
10.1016/j.cmet.2018.09.001
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发表时间：
2018-12-04
期刊：
影响因子：
29
通讯作者：
Topisirovic I
中科院分区：
文献类型：
--
作者：
Hulea L;Gravel SP;Morita M;Cargnello M;Uchenunu O;Im YK;Lehuédé C;Ma EH;Leibovitch M;McLaughlan S;Blouin MJ;Parisotto M;Papavasiliou V;Lavoie C;Larsson O;Ohh M;Ferreira T;Greenwood C;Bridon G;Avizonis D;Ferbeyre G;Siegel P;Jones RG;Muller W;Ursini-Siegel J;St-Pierre J;Pollak M;Topisirovic I
人们越来越关注在治疗上利用正常细胞和癌细胞之间的代谢差异。我们表明，激酶抑制剂（KIs）和双胍协同作用，并选择性地靶向各种癌细胞。非必需氨基酸（NEAA）天冬氨酸、天冬酰胺和丝氨酸的合成以及谷氨酰胺代谢是KI/双胍组合的功效的主要决定因素。mTORC 1/4 E-BP轴通过调节mRNA翻译来调节天冬氨酸、天冬酰胺和丝氨酸的合成，而4 E-BP 1/2的消融显著降低了乳腺癌和黑色素瘤细胞对KI/双胍组合的敏感性。KI/双胍组合的功效还通过在VHL缺陷型肾癌细胞中观察到的谷氨酰胺代谢中的HIF-1α依赖性扰动来确定。这表明癌细胞通过参与非冗余适应机制来显示代谢可塑性，这使得它们能够在靶向癌症代谢的治疗性损伤中存活。Hulea等人研究了激酶抑制剂（KI）和双胍类药物在靶向癌细胞中协同作用的机制，并表明涉及mTORC 1、4 E-BP和HIF 1a的不同途径在起作用。癌细胞通过参与非冗余的适应性机制来显示代谢可塑性，这使得它们能够在治疗组合中存活。
There is increasing interest to therapeutically exploit metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1α-dependent perturbations in glutamine metabolism which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms which allows them to survive therapeutic insults that target cancer metabolism. Hulea et al. investigate the mechanisms underlying the synergic efficacy of kinase inhibitors (KI) and biguanides in targeting cancer cells and show that different pathways involving mTORC1, 4E-BP and HIF1a are at play. Cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms which allows them to survive therapy combinations.
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影响因子：
29.4
作者：
Cummins, Eoin P.;Seeballuck, Fergal;Taylor, Cormac T.
通讯作者：
Taylor, Cormac T.
影响因子：
8
作者：
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影响因子：
13.6
作者：
DeBerardinis RJ;Chandel NS
通讯作者：
Chandel NS
影响因子：
29
作者：
Gameiro PA;Yang J;Metelo AM;Pérez-Carro R;Baker R;Wang Z;Arreola A;Rathmell WK;Olumi A;López-Larrubia P;Stephanopoulos G;Iliopoulos O
通讯作者：
Iliopoulos O
影响因子：
5.7
作者：
Clem, Brian;Telang, Sucheta;Chesney, Jason
通讯作者：
Chesney, Jason