Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH
Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH
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DOI：
10.1016/j.celrep.2016.09.052
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发表时间：
2016-10-11
期刊：
影响因子：
8.8
通讯作者：
Smolen, Gromoslaw A.
中科院分区：
文献类型：
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作者：
Allen, Eric L.;Ulanet, Danielle B.;Smolen, Gromoslaw A.
尽管肿瘤中的异常代谢已得到充分描述，但识别具有特定代谢脆弱性的癌症亚型仍然具有挑战性。在此，我们针对参与三羧酸（TCA）循环的酶进行了小干扰RNA（siRNA）筛选，并发现癌细胞对α - 酮戊二酸脱氢酶复合物的E1亚基OGDH存在一系列显著的依赖性。通过综合代谢组学方法，我们发现通过苹果酸 - 天冬氨酸穿梭的天冬氨酸利用差异，可作为在三维培养实验中OGDH是否为增殖所必需以及在异种移植肿瘤生长中是否必需的预测指标。这些发现凸显了天冬氨酸的回补作用，并且更广泛地表明，不同的营养利用模式能够识别出具有不同代谢依赖性的癌症亚型，以便进行潜在的药物干预。
Although aberrant metabolism in tumors has been well described, the identification of cancer subsets with particular metabolic vulnerabilities has remained challenging. Here, we conducted an siRNA screen focusing on enzymes involved in the tricarboxylic acid (TCA) cycle and uncovered a striking range of cancer cell dependencies on OGDH, the E1 subunit of the alpha-ketoglutarate dehydrogenase complex. Using an integrative metabolomics approach, we identified differential aspartate utilization, via the malate-aspartate shuttle, as a predictor of whether OGDH is required for proliferation in 3D culture assays and for the growth of xenograft tumors. These findings highlight an anaplerotic role of aspartate and, more broadly, suggest that differential nutrient utilization patterns can identify subsets of cancers with distinct metabolic dependencies for potential pharmacological intervention.