Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

被引：658

作者：

Anastasiou, Dimitrios ^{[1
,2
]}

Yu, Yimin ^{[3
]}

Israelsen, William J. ^{[3
]}

Jiang, Jian-Kang ^{[4
]}

Boxer, Matthew B. ^{[4
]}

Hong, Bum Soo ^{[5
]}

Tempel, Wolfram ^{[5
]}

Dimov, Svetoslav ^{[5
]}

Shen, Min ^{[4
]}

Jha, Abhishek ^{[6
]}

Yang, Hua ^{[7
]}

Mattaini, Katherine R. ^{[3
]}

Metallo, Christian M. ^{[8
]}

Fiske, Brian P. ^{[3
]}

Courtney, Kevin D. ^{[1
,2
,9
]}

Malstrom, Scott ^{[3
]}

Khan, Tahsin M. ^{[3
]}

Kung, Charles ^{[7
]}

Skoumbourdis, Amanda P. ^{[4
]}

Veith, Henrike ^{[4
]}

Southall, Noel ^{[4
]}

Walsh, Martin J. ^{[4
]}

Brimacombe, Kyle R. ^{[4
]}

Leister, William ^{[4
]}

Lunt, Sophia Y. ^{[3
]}

Johnson, Zachary R. ^{[3
]}

Yen, Katharine E. ^{[7
]}

Kunii, Kaiko ^{[7
]}

Davidson, Shawn M. ^{[3
]}

Christofk, Heather R. ^{[1
]}

Austin, Christopher P. ^{[4
]}

Inglese, James ^{[4
]}

Harris, Marian H. ^{[10
]}

Asara, John M. ^{[1
,11
]}

Stephanopoulos, Gregory ^{[6
]}

Salituro, Francesco G. ^{[7
]}

Jin, Shengfang ^{[7
]}

Dang, Lenny ^{[7
]}

Auld, Douglas S. ^{[4
]}

Park, Hee-Won ^{[5
,12
]}

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

Thomas, Craig J. ^{[4
]}

Heiden, Matthew G. Vander ^{[3
,9
]}

机构：

[1] Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA 02215 USA

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

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

[4] Natl Ctr Adv Translat Sci, NIH, Chem Genom Ctr, Bethesda, MD USA

[5] Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada

[6] MIT, Dept Chem Engn, Cambridge, MA 02139 USA

[7] Agios Pharmaceut, Cambridge, MA USA

[8] Univ Calif San Diego, Dept Bioengn, San Diego, CA 92103 USA

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

[10] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

[11] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[12] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada

来源：

NATURE CHEMICAL BIOLOGY | 2012年 / 8卷 / 10期

基金：

英国惠康基金;

关键词：

CANCER-CELL METABOLISM; TUMOR-GROWTH; NUCLEAR TRANSLOCATION; THYROID-HORMONE; BINDING PROTEIN; ISOFORM; FRUCTOSE-1,6-BISPHOSPHATE; ISOZYME; INHIBITION; CONVERSION;

D O I：

10.1038/NCHEMBIO.1060

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

引用

页码：839 / 847

页数：9

共 43 条

[1]

Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses [J].

Anastasiou, Dimitrios ;

Poulogiannis, George ;

Asara, John M. ;

Boxer, Matthew B. ;

Jiang, Jian-kang ;

Shen, Min ;

Bellinger, Gary ;

Sasaki, Atsuo T. ;

Locasale, Jason W. ;

Auld, Douglas S. ;

Thomas, Craig J. ;

Vander Heiden, Matthew G. ;

Cantley, Lewis C. .

SCIENCE, 2011, 334 (6060) :1278-1283

[2]

AN INVITRO NOVEL MECHANISM OF REGULATING THE ACTIVITY OF PYRUVATE KINASE-M2 BY THYROID-HORMONE AND FRUCTOSE-1,6-BISPHOSPHATE [J].

ASHIZAWA, K ;

MCPHIE, P ;

LIN, KH ;

CHENG, SY .

BIOCHEMISTRY, 1991, 30 (29) :7105-7111

[3]

ASHIZAWA K, 1991, J BIOL CHEM, V266, P16842

[4]

The Protein Data Bank [J].

Berman, HM ;

Westbrook, J ;

Feng, Z ;

Gilliland, G ;

Bhat, TN ;

Weissig, H ;

Shindyalov, IN ;

Bourne, PE .

NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :235-242

[5]

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

[6]

Regulation of cancer cell metabolism [J].

Cairns, Rob A. ;

Harris, Isaac S. ;

Mak, Tak W. .

NATURE REVIEWS CANCER, 2011, 11 (02) :85-95

[7]

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

[8]

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

[9]

The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism [J].

Clower, Cynthia V. ;

Chatterjee, Deblina ;

Wang, Zhenxun ;

Cantley, Lewis C. ;

Heiden, Matthew G. Vander ;

Krainer, Adrian R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (05) :1894-1899

[10]

MolProbity: structure validation and all-atom contact analysis for nucleic acids and their complexes [J].

Davis, IW ;

Murray, LW ;

Richardson, JS ;

Richardson, DC .

NUCLEIC ACIDS RESEARCH, 2004, 32 :W615-W619

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