2-Hydroxyglutarate in Cancer Cells.
2-Hydroxyglutarate in Cancer Cells.
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DOI：
10.1089/ars.2019.7902
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发表时间：
2020-11-01
影响因子：
6.6
通讯作者：
Ježek P
中科院分区：
文献类型：
--
作者：
Ježek P
意义：癌细胞稳定在类似于干细胞的未分化状态。这导致其代谢的深刻改变，随着恶性肿瘤的进展，这进一步改变了其遗传学和表观遗传学。特定的代谢物和酶可以作为癌症进展的临床标志物。最新进展：两种2-羟基戊二酸（2 HG）对映异构体都与III/IV级胶质瘤、胶质母细胞瘤和急性髓性白血病细胞以及许多其他癌症类型中的重编程代谢相关，同时也在肿瘤与免疫细胞的相互作用中起作用。2 HG有助于癌症代谢和发展的氧化应激的特定变化，同时还诱导幼稚T淋巴细胞分化的决定，并作为免疫细胞中的信号信使。此外，2 HG抑制染色质修饰酶，即2-酮戊二酸依赖性双加氧酶，并干扰缺氧诱导因子（HIF）转录组重编程和哺乳动物雷帕霉素靶蛋白（mTOR）途径，从而失调基因表达并进一步促进癌症发生。关键问题：通常，异柠檬酸脱氢酶亚型1（IDH 1）R132 H和线粒体异柠檬酸脱氢酶亚型2（IDH 2）R140 Q的活性位点内的杂合突变为细胞提供了毫摩尔r-2-羟基戊二酸（r-2 HG）浓度，而乳酸和苹果酸脱氢酶的副活性形成亚毫摩尔s-2-羟基戊二酸（s-2 HG）。然而，即使是野生型IDH 1和IDH 2，特别是在还原性羧化脱氢酶或其他酶的变化下，也会导致“中间”0.01-0.1 mM的2 HG水平，例如，在乳腺癌中，与非癌细胞中的10−8 M相比。未来发展方向：发现特定于给定癌细胞类型和序列特异性表观遗传改变的进一步分子代谢细节将导致诊断方法的设计，不仅用于预测患者的预后或发现转移和肿瘤缓解，而且用于早期诊断。
Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1)R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2)R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to “intermediate” 0.01–0.1 mM 2HG levels, for example, in breast carcinoma compared with 10−8 M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics.
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影响因子：
16.6
作者：
Carbonneau, Melissa;Gagne, Laurence M.;Lalonde, Marie-Eve;Germain, Marie-Anne;Motorina, Alena;Guiot, Marie-Christine;Secco, Blandine;Vincent, Emma E.;Tumber, Anthony;Hulea, Laura;Bergeman, Jonathan;Oppermann, Udo;Jones, Russell G.;Laplante, Mathieu;Topisirovic, Ivan;Petrecca, Kevin;Huot, Marc-Etienne;Mallette, Frederick A.
通讯作者：
Mallette, Frederick A.
影响因子：
4.8
作者：
Ceccarelli, C;Grodsky, NB;Bahnson, BJ
通讯作者：
Bahnson, BJ
影响因子：
56.9
作者：
Chakraborty, Abhishek A.;Laukka, Tuomas;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
影响因子：
6.2
作者：
Brunner, Andrew M.;Neuberg, Donna S.;Fathi, Amir T.
通讯作者：
Fathi, Amir T.
影响因子：
7.1
作者：
Ballester LY;Lu G;Zorofchian S;Vantaku V;Putluri V;Yan Y;Arevalo O;Zhu P;Riascos RF;Sreekumar A;Esquenazi Y;Putluri N;Zhu JJ
通讯作者：
Zhu JJ