IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism.
IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism.
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DOI：
10.1158/0008-5472.can-14-0772-t
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发表时间：
2014-06-15
期刊：
影响因子：
11.2
通讯作者：
Metallo CM
中科院分区：
文献类型：
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作者：
Grassian AR;Parker SJ;Davidson SM;Divakaruni AS;Green CR;Zhang X;Slocum KL;Pu M;Lin F;Vickers C;Joud-Caldwell C;Chung F;Yin H;Handly ED;Straub C;Growney JD;Vander Heiden MG;Murphy AN;Pagliarini R;Metallo CM
异柠檬酸脱氢酶1和异柠檬酸脱氢酶2(IDH1/2)的癌基因突变存在于多种类型的癌症中，但这些基因变化的代谢后果尚不完全清楚。在这项研究中，我们对一组含有IDH1/2杂合突变的等基因细胞系进行了13C代谢通量分析。我们观察到，在低氧条件下，IDH1突变细胞表现出氧化三羧酸代谢增加，还原谷氨酰胺代谢降低，但IDH2突变细胞没有。然而，选择性抑制突变的IDH1酶功能并不能逆转还原羧化活性的缺陷。此外，在体外，这种代谢重编程增加了IDH1突变细胞对低氧或电子传递链抑制的敏感性。最后，IDH1突变细胞在体内低氧微环境中作为皮下异种移植细胞生长也很差。总而言之，我们的结果表明有机会利用IDH1突变特有的代谢脆弱性。
Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed 13C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation.