Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

被引：135

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：

071009 ; 090102 ;

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

共 71 条

[1]

Ahn CS, 2015, CANCER METAB, V3, DOI 10.1186/s40170-015-0128-2

[2] AGC1/2, the mitochondrial aspartate-glutamate carriers [J].

Amoedo, N. D. ;

Punzi, G. ;

Obre, E. ;

Lacombe, D. ;

De Grassi, A. ;

Pierri, C. L. ;

Rossignol, R. .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2016, 1863 (10) :2394-2412

[3] Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse [J].

Bardeesy, N ;

Aguirre, AJ ;

Chu, GC ;

Cheng, KH ;

Lopez, LV ;

Hezel, AF ;

Feng, B ;

Brennan, C ;

Weissleder, R ;

Mahmood, U ;

Hanahan, D ;

Redston, MS ;

Chin, L ;

DePinho, RA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (15) :5947-5952

[4] Expression of three mitochondrial solute carriers, citrin, aralarl and ornithine transporter, in relation to urea cycle in mice [J].

Begum, L ;

Jalil, MA ;

Kobayashi, K ;

Iijima, M ;

Li, MX ;

Yasuda, T ;

Horiuchi, M ;

del Arco, A ;

Satrústegui, J ;

Saheki, T .

BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 2002, 1574 (03) :283-292

[5] Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism [J].

Biancur, Douglas E. ;

Paulo, Joao A. ;

Malachowska, Beata ;

Del Rey, Maria Quiles ;

Sousa, Cristovao M. ;

Wang, Xiaoxu ;

Sohn, Albert S. W. ;

Chu, Gerald C. ;

Gygi, Steven P. ;

Harper, J. Wade ;

Fendler, Wojciech ;

Mancias, Joseph D. ;

Kimmelman, Alec C. .

NATURE COMMUNICATIONS, 2017, 8

[6] An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis [J].

Birsoy, Kivanc ;

Wang, Tim ;

Chen, Walter W. ;

Freinkman, Elizaveta ;

Abu-Remaileh, Monther ;

Sabatini, David M. .

CELL, 2015, 162 (03) :540-551

[7] Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase [J].

Cantor, Jason R. ;

Abu-Remaileh, Monther ;

Kanarek, Naama ;

Freinkman, Elizaveta ;

Gao, Xin ;

Louissaint, Abner, Jr. ;

Lewis, Caroline A. ;

Sabatini, David M. .

CELL, 2017, 169 (02) :258-272

[8] Cancer Cell Metabolism: One Hallmark, Many Faces [J].

Cantor, Jason R. ;

Sabatini, David M. .

CANCER DISCOVERY, 2012, 2 (10) :881-898

[9] Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism [J].

Cassago, Alexandre ;

Ferreira, Amanda P. S. ;

Ferreira, Igor M. ;

Fornezari, Camila ;

Gomes, Emerson R. M. ;

Greene, Kai Su ;

Pereira, Humberto M. ;

Garratt, Richard C. ;

Dias, Sandra M. G. ;

Ambrosio, Andre L. B. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (04) :1092-1097

[10]

Catalina-Rodriguez O, 2012, ONCOTARGET, V3, P1220

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