Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent Anaplerosis

被引：201

作者：

Christen, Stefan ^{[1
,2
,3
]}

Lorendeau, Doriane ^{[1
,2
,3
]}

Schmieder, Roberta ^{[1
,2
,3
]}

Broekaert, Dorien ^{[1
,2
,3
]}

Metzger, Kristine ^{[1
,2
,3
]}

Veys, Koen ^{[4
,5
]}

Elia, Ilaria ^{[1
,2
,3
]}

Buescher, Joerg Martin ^{[1
,2
,3
]}

Orth, Martin Franz ^{[6
]}

Davidson, Shawn Michael ^{[7
]}

Gruenewald, Thomas Georg Philipp ^{[6
]}

De Bock, Katrien ^{[8
]}

Fendt, Sarah-Maria ^{[1
,2
,3
]}

机构：

[1] VIB, Vesalius Res Ctr, Lab Cellular Metab & Metab Regulat, Herestr 49, B-3000 Leuven, Belgium

[2] Katholieke Univ Leuven, Dept Oncol, Lab Cellular Metab & Metab Regulat, Herestr 49, B-3000 Leuven, Belgium

[3] LKI, Leuven Canc Inst, Herestr 49, B-3000 Leuven, Belgium

[4] Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49, B-3000 Leuven, Belgium

[5] VIB, Vesalius Res Ctr, Herestr 49, B-3000 Leuven, Belgium

[6] Ludwig Maximilians Univ Munchen, Inst Pathol, Max Eder Res Grp Pediat Sarcoma Biol, Thalkirchner Str 36, D-80337 Munich, Germany

[7] MIT, David H Koch Inst Integrat Canc Res, 500 Main St, Cambridge, MA 02139 USA

[8] Swiss Fed Inst Technol, Dept Hlth Sci & Technol, Lab Exercise & Hlth, Schorenstr 16, CH-8603 Schwerzenbach, Switzerland

来源：

CELL REPORTS | 2016年 / 17卷 / 03期

关键词：

SUBSTRATE ACTIVATION; INDEPENDENT GROWTH; METABOLISM; CELLS; INHIBITION; MAINTAINS; OXIDATION; PATHWAYS; CARRIER; ENZYME;

D O I：

10.1016/j.celrep.2016.09.042

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：

Cellular proliferation depends on refilling the tricarboxylic acid (TCA) cycle to support biomass production (anaplerosis). The two major anaplerotic pathways in cells are pyruvate conversion to oxaloacetate via pyruvate carboxylase (PC) and glutamine conversion to a-ketoglutarate. Cancers often show an organ-specific reliance on either pathway. However, it remains unknown whether they adapt their mode of anaplerosis when metastasizing to a distant organ. We measured PC-dependent anaplerosis in breast-cancer-derived lung metastases compared to their primary cancers using in vivo C-13 tracer analysis. We discovered that lung metastases have higher PC-dependent anaplerosis compared to primary breast cancers. Based on in vitro analysis and a mathematical model for the determination of compartment-specific metabolite concentrations, we found that mitochondrial pyruvate concentrations can promote PC-dependent anaplerosis via enzyme kinetics. In conclusion, we show that breast cancer cells proliferating as lung metastases activate PC-dependent anaplerosis in response to the lung microenvironment.

引用

页码：837 / 848

页数：12

共 38 条

[1]

Regulation of the structure and activity of pyruvate carboxylase by acetyl CoA [J].

Adina-Zada, Abdussalam ;

Zeczycki, Tonya N. ;

Attwood, Paul V. .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2012, 519 (02) :118-130

[2]

Elementary metabolite units (EMU): A novel framework for modeling isotopic distributions [J].

Antoniewicz, Maciek R. ;

Kelleher, Joanne K. ;

Stephanopoulos, Gregory .

METABOLIC ENGINEERING, 2007, 9 (01) :68-86

[3]

Transcriptional regulation of the distal promoter of the rat pyruvate carboxylase gene by hepatocyte nuclear factor 3β/Foxa2 and upstream stimulatory factors in insulinoma cells [J].

Boonsaen, Thirajit ;

Rojvirat, Pinnara ;

Surinya, Kathy H. ;

Wallace, John C. ;

Jitrapakdee, Sarawut .

BIOCHEMICAL JOURNAL, 2007, 405 :359-367

[4]

A roadmap for interpreting 13C metabolite labeling patterns from cells [J].

Buescher, Joerg M. ;

Antoniewicz, Maciek R. ;

Boros, Laszlo G. ;

Burgess, Shawn C. ;

Brunengraber, Henri ;

Clish, Clary B. ;

DeBerardinis, Ralph J. ;

Feron, Olivier ;

Frezza, Christian ;

Ghesquiere, Bart ;

Gottlieb, Eyal ;

Hiller, Karsten ;

Jones, Russell G. ;

Kamphorst, Jurre J. ;

Kibbey, Richard G. ;

Kimmelman, Alec C. ;

Locasale, Jason W. ;

Lunt, Sophia Y. ;

Maddocks, Oliver D. K. ;

Malloy, Craig ;

Metallo, Christian M. ;

Meuillet, Emmanuelle J. ;

Munger, Joshua ;

Noeh, Katharina ;

Rabinowitz, Joshua D. ;

Ralser, Markus ;

Sauer, Uwe ;

Stephanopoulos, Gregory ;

St-Pierre, Julie ;

Tennant, Daniel A. ;

Wittmann, Christoph ;

Vander Heiden, Matthew G. ;

Vazquez, Alexei ;

Vousden, Karen ;

Young, Jamey D. ;

Zamboni, Nicola ;

Fendt, Sarah-Maria .

CURRENT OPINION IN BIOTECHNOLOGY, 2015, 34 :189-201

[5]

Gain of Glucose-Independent Growth upon Metastasis of Breast Cancer Cells to the Brain [J].

Chen, Jinyu ;

Lee, Ho-Jeong ;

Wu, Xuefeng ;

Huo, Lei ;

Kim, Sun-Jin ;

Xu, Lei ;

Wang, Yan ;

He, Junqing ;

Bollu, Lakshmi R. ;

Gao, Guang ;

Su, Fei ;

Briggs, James ;

Liu, Xiaojing ;

Melman, Tamar ;

Asara, John M. ;

Fidler, Isaiah J. ;

Cantley, Lewis C. ;

Locasale, Jason W. ;

Zhang Weihua .

CANCER RESEARCH, 2015, 75 (03) :554-565

[6]

Pyruvate carboxylase is required for glutamine-independent growth of tumor cells [J].

Cheng, Tzuling ;

Sudderth, Jessica ;

Yang, Chendong ;

Mullen, Andrew R. ;

Jin, Eunsook S. ;

Mates, Jose M. ;

DeBerardinis, Ralph J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (21) :8674-8679

[7]

Monitoring Mitochondrial Pyruvate Carrier Activity in Real Time Using a BRET-Based Biosensor: Investigation of the Warburg Effect [J].

Compan, Vincent ;

Pierredon, Sandra ;

Vanderperre, Benoit ;

Krznar, Petra ;

Marchiq, Ibtissam ;

Zamboni, Nicola ;

Pouyssegur, Jacques ;

Martinou, Jean-Claude .

MOLECULAR CELL, 2015, 59 (03) :491-501

[8]

Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer [J].

Davidson, Shawn M. ;

Papagiannakopoulos, Thales ;

Olenchock, Benjamin A. ;

Heyman, Julia E. ;

Keibler, Mark A. ;

Luengo, Alba ;

Bauer, Matthew R. ;

Jha, Abhishek K. ;

O'Brien, James P. ;

Pierce, Kerry A. ;

Gui, Dan Y. ;

Sullivan, Lucas B. ;

Wasylenko, Thomas M. ;

Subbaraj, Lakshmipriya ;

Chin, Christopher R. ;

Stephanopolous, Gregory ;

Mott, Bryan T. ;

Jacks, Tyler ;

Clish, Clary B. ;

Heiden, Matthew G. Vander .

CELL METABOLISM, 2016, 23 (03) :517-528

[9]

Brick by brick: metabolism and tumor cell growth [J].

DeBerardinis, Ralph J. ;

Sayed, Nabil ;

Ditsworth, Dara ;

Thompson, Craig B. .

CURRENT OPINION IN GENETICS & DEVELOPMENT, 2008, 18 (01) :54-61

[10]

PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer [J].

Dupuy, Fanny ;

Tabaries, Sebastien ;

Andrzejewski, Sylvia ;

Dong, Zhifeng ;

Blagih, Julianna ;

Annis, Matthew G. ;

Omeroglu, Atilla ;

Gao, Dongxia ;

Leung, Samuel ;

Amir, Eitan ;

Clemons, Mark ;

Aguilar-Mahecha, Adriana ;

Basik, Mark ;

Vincent, Emma E. ;

St-Pierre, Julie ;

Jones, Russell G. ;

Siegel, Peter M. .

CELL METABOLISM, 2015, 22 (04) :577-589

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