Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH

被引：61

作者：

Allen, Eric L. ^{[1
]}

Ulanet, Danielle B. ^{[1
]}

Pirman, David ^{[1
]}

Mahoney, Christopher E. ^{[1
]}

Coco, John ^{[1
]}

Si, Yaguang ^{[1
]}

Chen, Ying ^{[2
]}

Huang, Lingling ^{[2
]}

Ren, Jinmin ^{[2
]}

Choe, Sung ^{[1
]}

Clasquin, Michelle F. ^{[1
]}

Artin, Erin ^{[1
]}

Fan, Zi Peng ^{[1
]}

Cianchetta, Giovanni ^{[1
]}

Murtie, Joshua ^{[1
]}

Dorsch, Marion ^{[1
]}

Jin, Shengfang ^{[1
]}

Smolen, Gromoslaw A. ^{[1
]}

机构：

[1] Agios Pharmaceut, 88 Sidney St, Cambridge, MA 02139 USA

[2] Shanghai ChemPartner Co Ltd, 998 Halei Rd, Shanghai 201203, Peoples R China

来源：

CELL REPORTS | 2016年 / 17卷 / 03期

关键词：

ALPHA-KETOGLUTARATE DEHYDROGENASE; GLUTAMINE-METABOLISM; REDUCTIVE CARBOXYLATION; PROTEIN; BIOSYNTHESIS; SUBUNIT; COMPLEX; CITRATE; GROWTH; BRAIN;

D O I：

10.1016/j.celrep.2016.09.052

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：876 / 890

页数：15

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