Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses

被引：1036

作者：

Anastasiou, Dimitrios ^{[1
,2
]}

Poulogiannis, George ^{[1
,2
]}

Asara, John M. ^{[1
,3
]}

Boxer, Matthew B. ^{[4
]}

Jiang, Jian-kang ^{[4
]}

Shen, Min ^{[4
]}

Bellinger, Gary ^{[1
,5
]}

Sasaki, Atsuo T. ^{[1
,2
]}

Locasale, Jason W. ^{[1
,2
]}

Auld, Douglas S. ^{[4
]}

Thomas, Craig J. ^{[4
]}

Vander Heiden, Matthew G. ^{[5
,6
]}

Cantley, Lewis C. ^{[1
,2
]}

机构：

[1] Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[4] NHGRI, NIH Chem Genom Ctr, NIH, Rockville, MD 20850 USA

[5] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[6] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA

来源：

SCIENCE | 2011年 / 334卷 / 6060期

基金：

美国国家卫生研究院;

关键词：

OXIDATIVE STRESS; TUMOR-SUPPRESSOR; CELLS; ROS; METABOLISM; CANCER; ISOFORM; PROTEIN;

D O I：

10.1126/science.1211485

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. We show that, in human lung cancer cells, acute increases in intracellular concentrations of ROS caused inhibition of the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation of Cys(358). This inhibition of PKM2 is required to divert glucose flux into the pentose phosphate pathway and thereby generate sufficient reducing potential for detoxification of ROS. Lung cancer cells in which endogenous PKM2 was replaced with the Cys(358) to Ser(358) oxidation-resistant mutant exhibited increased sensitivity to oxidative stress and impaired tumor formation in a xenograft model. Besides promoting metabolic changes required for proliferation, the regulatory properties of PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress.

引用

页码：1278 / 1283

页数：6

共 28 条

[1]

Modulation of intracellular ROS levels by TIGAR controls autophagy [J].

Bensaad, Karim ;

Cheung, Eric C. ;

Vousden, Karen H. .

EMBO JOURNAL, 2009, 28 (19) :3015-3026

[2]

Evaluation of Substituted N,N′-Diarylsulfonamides as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate Kinase [J].

Boxer, Matthew B. ;

Jiang, Jian-kang ;

Vander Heiden, Matthew G. ;

Shen, Min ;

Skoumbourdis, Amanda P. ;

Southall, Noel ;

Veith, Henrike ;

Leister, William ;

Austin, Christopher P. ;

Park, Hee Won ;

Inglese, James ;

Cantley, Lewis C. ;

Auld, Douglas S. ;

Thomas, Craig J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (03) :1048-1055

[3]

Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation [J].

Brunelle, JK ;

Bell, EL ;

Quesada, NM ;

Vercauteren, K ;

Tiranti, V ;

Zeviani, M ;

Scarpulla, RC ;

Chandel, NS .

CELL METABOLISM, 2005, 1 (06) :409-414

[4]

Butterfield DA, 2007, J ALZHEIMERS DIS, V12, P61

[5]

The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth [J].

Christofk, Heather R. ;

Vander Heiden, Matthew G. ;

Harris, Marian H. ;

Ramanathan, Arvind ;

Gerszten, Robert E. ;

Wei, Ru ;

Fleming, Mark D. ;

Schreiber, Stuart L. ;

Cantley, Lewis C. .

NATURE, 2008, 452 (7184) :230-U74

[6]

Pyruvate kinase M2 is a phosphotyrosine-binding protein [J].

Christofk, Heather R. ;

Vander Heiden, Matthew G. ;

Wu, Ning ;

Asara, John M. ;

Cantley, Lewis C. .

NATURE, 2008, 452 (7184) :181-U27

[7]

Protein disulfide bond formation in the cytoplasm during oxidative stress [J].

Cumming, RC ;

Andon, NL ;

Haynes, PA ;

Park, M ;

Fischer, WH ;

Schubert, D .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (21) :21749-21758

[8]

Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis [J].

Dombrauckas, JD ;

Santarsiero, BD ;

Mesecar, AD .

BIOCHEMISTRY, 2005, 44 (27) :9417-9429

[9]

EIGENBRODT E, 1992, Critical Reviews in Oncogenesis, V3, P91

[10]

Failure to increase glucose consumption through the pentose-phosphate pathway results in the death of glucose-6-phosphate dehydrogenase gene-deleted mouse embryonic stem cells subjected to oxidative stress [J].

Filosa, S ;

Fico, A ;

Paglialunga, F ;

Balestrieri, M ;

Crooke, A ;

Verde, P ;

Abrescia, P ;

Bautista, JM ;

Martini, G .

BIOCHEMICAL JOURNAL, 2003, 370 :935-943

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