Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells

被引：253

作者：

Coloff, Jonathan L. ^{[1
]}

Murphy, J. Patrick ^{[1
]}

Braun, Craig R. ^{[1
]}

Harris, Isaac S. ^{[1
]}

Shelton, Laura M. ^{[2
]}

Kami, Kenjiro ^{[3
]}

Gygi, Steven P. ^{[1
]}

Selfors, Laura M. ^{[1
]}

Brugge, Joan S. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[2] Human Metabolome Technol Amer, Boston, MA 02134 USA

[3] Human Metabolome Technol, Tsuruoka, Yamagata 9970052, Japan

来源：

CELL METABOLISM | 2016年 / 23卷 / 05期

关键词：

AEROBIC GLYCOLYSIS; GLUCOSE-METABOLISM; CANCER; GROWTH; PATHWAY; PROTEIN; CYCLE; GLUTAMINOLYSIS; BIOSYNTHESIS; ANTIOXIDANT;

D O I：

10.1016/j.cmet.2016.03.016

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：

Mammary epithelial cells transition between periods of proliferation and quiescence during development, menstrual cycles, and pregnancy, and as a result of oncogenic transformation. Utilizing an organotypic 3D tissue culture model coupled with quantitative metabolomics and proteomics, we identified significant differences in glutamate utilization between proliferating and quiescent cells. Relative to quiescent cells, proliferating cells catabolized more glutamate via transaminases to couple non-essential amino acid (NEAA) synthesis to alpha-ketoglutarate generation and tricarboxylic acid (TCA) cycle anaplerosis. As cells transitioned to quiescence, glutamine consumption and transaminase expression were reduced, while glutamate dehydrogenase (GLUD) was induced, leading to decreased NEAA synthesis. Highly proliferative human tumors display high transaminase and low GLUD expression, suggesting that proliferating cancer cells couple glutamine consumption to NEAA synthesis to promote biosynthesis. These findings describe a competitive and partially redundant relationship between transaminases and GLUD, and they reveal how coupling of glutamate-derived carbon and nitrogen metabolism can be regulated to support cell proliferation.

引用

页码：867 / 880

页数：14

共 56 条

[1]

Role of the transcription factor ATF4 in the anabolic actions of insulin and the anti-anabolic actions of glucocorticoids [J].

Adams, Christopher M. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (23) :16744-16753

[2]

ENERGY CHARGE OF ADENYLATE POOL AS A REGULATORY PARAMETER . INTERACTION WITH FEEDBACK MODIFIERS [J].

ATKINSON, DE .

BIOCHEMISTRY, 1968, 7 (11) :4030-&

[3]

Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis [J].

Cardaci, Simone ;

Zheng, Liang ;

MacKay, Gillian ;

Van den Broek, Niels J. F. ;

MacKenzie, Elaine D. ;

Nixon, Colin ;

Stevenson, David ;

Tumanov, Sergey ;

Bulusu, Vinay ;

Kamphorst, Jurre J. ;

Vazquez, Alexei ;

Fleming, Stewart ;

Schiavi, Francesca ;

Kalna, Gabriela ;

Blyth, Karen ;

Strathdee, Douglas ;

Gottlieb, Eyal .

NATURE CELL BIOLOGY, 2015, 17 (10) :1317-+

[4]

The Essence of Quiescence [J].

Coller, Hilary A. .

SCIENCE, 2011, 334 (6059) :1074-1075

[5]

The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 [J].

Csibi, Alfred ;

Fendt, Sarah-Maria ;

Li, Chenggang ;

Poulogiannis, George ;

Choo, Andrew Y. ;

Chapski, Douglas J. ;

Jeong, Seung Min ;

Dempsey, Jamie M. ;

Parkhitko, Andrey ;

Morrison, Tasha ;

Henske, Elizabeth P. ;

Haigis, Marcia C. ;

Cantley, Lewis C. ;

Stephanopoulos, Gregory ;

Yu, Jane ;

Blenis, John .

CELL, 2013, 153 (04) :840-854

[6]

The mTORC1/S6K1 Pathway Regulates Glutamine Metabolism through the elF4B-Dependent Control of c-Myc Translation [J].

Csibi, Alfredo ;

Lee, Gina ;

Yoon, Sang-Oh ;

Tong, Haoxuan ;

Iiter, Didem ;

Elia, Ilaria ;

Fendt, Sarah-Maria ;

Roberts, Thomas M. ;

Blenis, John .

CURRENT BIOLOGY, 2014, 24 (19) :2274-2280

[7]

Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis [J].

DeBerardinis, Ralph J. ;

Mancuso, Anthony ;

Daikhin, Evgueni ;

Nissim, Ilana ;

Yudkoff, Marc ;

Wehrli, Suzanne ;

Thompson, Craig B. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (49) :19345-19350

[8]

Modelling glandular epithelial cancers in three-dimensional cultures [J].

Debnath, J ;

Brugge, JS .

NATURE REVIEWS CANCER, 2005, 5 (09) :675-688

[9]

NRF2 regulates serine biosynthesis in non-small cell lung cancer [J].

DeNicola, Gina M. ;

Chen, Pei-Hsuan ;

Mullarky, Edouard ;

Sudderth, Jessica A. ;

Hu, Zeping ;

Wu, David ;

Tang, Hao ;

Xie, Yang ;

Asara, John M. ;

Huffman, Kenneth E. ;

Wistuba, Ignacio I. ;

Minna, John D. ;

DeBerardinis, Ralph J. ;

Cantley, Lewis C. .

NATURE GENETICS, 2015, 47 (12) :1475-+

[10]

Signal integration by mTORC1 coordinates nutrient input with biosynthetic output [J].

Dibble, Christian C. ;

Manning, Brendan D. .

NATURE CELL BIOLOGY, 2013, 15 (06) :555-564

← 1 2 3 4 5 6 →