Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

被引：151

作者：

Alkan, H. Furkan ^{[1
,2
,3
]}

Walter, Katharina E. ^{[1
]}

Luengo, Alba ^{[2
,3
]}

Madreiter-Sokolowski, Corina T. ^{[4
]}

Stryeck, Sarah ^{[4
]}

Lau, Allison N. ^{[2
,3
]}

Al-Zoughbi, Wael ^{[5
]}

Lewis, Caroline A. ^{[6
]}

Thomas, Craig J. ^{[7
,8
]}

Hoefler, Gerald ^{[5
,9
]}

Graier, Wolfgang F. ^{[4
,9
]}

Madl, Tobias ^{[4
,9
]}

Vander Heiden, Matthew G. ^{[2
,3
,10
]}

Bogner-Strauss, Juliane G. ^{[1
,9
]}

机构：

[1] Graz Univ Technol, Inst Biochem, Humboldtstr 46-3, A-8010 Graz, Austria

[2] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[3] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[4] Med Univ Graz, Gottfried Schatz Res Ctr, Mol Biol & Biochem, Neue Stiftingtalstr 6-6, A-8010 Graz, Austria

[5] Med Univ Graz, Diagnost & Res Inst Pathol, Neue Stiftingtalstr 6, A-8010 Graz, Austria

[6] Whitehead Inst Biomed Res, 455 Main St, Cambridge, MA 02142 USA

[7] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA

[8] NCI, Lymphoid Malignancies Branch, Bethesda, MD 20892 USA

[9] BioTechMed Graz, Graz, Austria

[10] Dana Farber Canc Inst, Boston, MA 02115 USA

来源：

CELL METABOLISM | 2018年 / 28卷 / 05期

基金：

奥地利科学基金会;

关键词：

REDUCED N-ACETYLASPARTATE; PANCREATIC ADENOCARCINOMA; MAMMALIAN-CELLS; CANCER-CELLS; LUNG-CANCER; AMINO-ACIDS; MITOCHONDRIA; METABOLISM; DEFICIENCY; CARRIERS;

D O I：

10.1016/j.cmet.2018.07.021

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Mitochondrial function is important for aspartate biosynthesis in proliferating cells. Here, we show that mitochondrial aspartate export via the aspartate-glutamate carrier 1 (AGC1) supports cell proliferation and cellular redox homeostasis. Insufficient cytosolic aspartate delivery leads to cell death when TCA cycle carbon is reduced following glutamine withdrawal and/or glutaminase inhibition. Moreover, loss of AGC1 reduces allograft tumor growth that is further compromised by treatment with the glutaminase inhibitor CB-839. Together, these findings argue that mitochondrial aspartate export sustains cell survival in low-glutamine environments and AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth.

引用

页码：706 / +

页数：21

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