Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition

被引:234
作者
Muir, Alexander [1 ,2 ]
Danai, Laura V. [1 ,2 ]
Gui, Dan Y. [1 ,2 ]
Waingarten, Chiara Y. [1 ,2 ]
Lewis, Caroline A. [3 ]
Heidan, Mathew G. Vander [1 ,2 ,4 ]
机构
[1] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA
[2] MIT, Dept Biol, Cambridge, MA USA
[3] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA
[4] Dana Farber Canc Inst, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
AMINO-ACID TRANSPORTERS; METABOLIC HETEROGENEITY; NUCLEOTIDE BIOSYNTHESIS; MEMBRANE TRANSPORTERS; PYRUVATE-CARBOXYLASE; GLUCOSE; GROWTH; LUNG; PROLIFERATION; TUMORS;
D O I
10.7554/eLife.27713
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Many mammalian cancer cell lines depend on glutamine as a major tri-carboxylic acid (TCA) cycle anaplerotic substrate to support proliferation. However, some cell lines that depend on glutamine anaplerosis in culture rely less on glutamine catabolism to proliferate in vivo. We sought to understand the environmental differences that cause differential dependence on glutamine for anaplerosis. We find that cells cultured in adult bovine serum, which better reflects nutrients available to cells in vivo, exhibit decreased glutamine catabolism and reduced reliance on glutamine anaplerosis compared to cells cultured in standard tissue culture conditions. We find that levels of a single nutrient, cystine, accounts for the differential dependence on glutamine in these different environmental contexts. Further, we show that cystine levels dictate glutamine dependence via the cystine/glutamate antiporter xCT/SLC7A11. Thus, xCT/SLC7A11 expression, in conjunction with environmental cystine, is necessary and sufficient to increase glutamine catabolism, defining important determinants of glutamine anaplerosis and glutaminase dependence in cancer.
引用
收藏
页数:27
相关论文
共 85 条
[41]   Metabolite Profiling Identifies a Key Role for Glycine in Rapid Cancer Cell Proliferation [J].
Jain, Mohit ;
Nilsson, Roland ;
Sharma, Sonia ;
Madhusudhan, Nikhil ;
Kitami, Toshimori ;
Souza, Amanda L. ;
Kafri, Ran ;
Kirschner, Marc W. ;
Clish, Clary B. ;
Mootha, Vamsi K. .
SCIENCE, 2012, 336 (6084) :1040-1044
[42]   Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth [J].
Jin, Lingtao ;
Li, Dan ;
Alesi, Gina N. ;
Fan, Jun ;
Kang, Hee-Bum ;
Lu, Zhou ;
Boggon, Titus J. ;
Jin, Peng ;
Yi, Hong ;
Wright, Elizabeth R. ;
Duc Duong ;
Seyfried, Nicholas T. ;
Egnatchik, Robert ;
DeBerardinis, Ralph J. ;
Magliocca, Kelly R. ;
He, Chuan ;
Arellano, Martha L. ;
Khoury, Hanna J. ;
Shin, Dong M. ;
Khuri, Fadlo R. ;
Kang, Sumin .
CANCER CELL, 2015, 27 (02) :257-270
[43]  
KANG YJ, 1991, CELL BIOL TOXICOL, V7, P249
[44]   GLUTATHIONE STIMULATES A549 CELL-PROLIFERATION IN GLUTAMINE-DEFICIENT CULTURE - THE EFFECT OF GLUTAMATE SUPPLEMENTATION [J].
KANG, YJ ;
FENG, Y ;
HATCHER, EL .
JOURNAL OF CELLULAR PHYSIOLOGY, 1994, 161 (03) :589-596
[45]  
KREBS HANS ADOLF, 1935, BIOCHEM JOUR, V29, P1951
[46]  
Lane AN, 2015, BIOPROTOCOL, V5, pe1650
[47]   Glucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells [J].
Le, Anne ;
Lane, Andrew N. ;
Hamaker, Max ;
Bose, Sminu ;
Gouw, Arvin ;
Barbi, Joseph ;
Tsukamoto, Takashi ;
Rojas, Camilio J. ;
Slusher, Barbara S. ;
Zhang, Haixia ;
Zimmerman, Lisa J. ;
Liebler, Daniel C. ;
Slebos, Robbert J. C. ;
Lorkiewicz, Pawel K. ;
Higashi, Richard M. ;
Fan, Teresa W. M. ;
Dang, Chi V. .
CELL METABOLISM, 2012, 15 (01) :110-121
[48]   Glutaminase 1 inhibition reduces thymidine synthesis in NSCLC [J].
Lee, Jae-Seon ;
Kang, Joon H. ;
Lee, Seon-Hyeong ;
Lee, Chang-Hun ;
Son, Jaekyoung ;
Kim, Soo-Youl .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2016, 477 (03) :374-382
[49]   The Cystine/Glutamate Antiporter System xc- in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities [J].
Lewerenz, Jan ;
Hewett, Sandra J. ;
Huang, Ying ;
Lambros, Maria ;
Gout, Peter W. ;
Kalivas, Peter W. ;
Massie, Ann ;
Smolders, Ilse ;
Methner, Axel ;
Pergande, Mathias ;
Smith, Sylvia B. ;
Ganapathy, Vadivel ;
Maher, Pamela .
ANTIOXIDANTS & REDOX SIGNALING, 2013, 18 (05) :522-555
[50]   Tracing Compartmentalized NADPH Metabolism in the Cytosol and Mitochondria of Mammalian Cells [J].
Lewis, Caroline A. ;
Parker, Seth J. ;
Fiske, Brian P. ;
McCloskey, Douglas ;
Gui, Dan Y. ;
Green, Courtney R. ;
Vokes, Natalie I. ;
Feist, Adam M. ;
Vander Heiden, Matthew G. ;
Metallo, Christian M. .
MOLECULAR CELL, 2014, 55 (02) :253-263