title: Cancer metabolism meets systems biology: Pyruvate kinase isoform PKM2 is a metabolic master regulator.
abstract: Pyruvate kinase activity is controlled by a tightly woven regulatory network. The oncofetal isoform of pyruvate kinase (PKM2) is a master regulator of cancer metabolism. PKM2 engages in parallel, feed-forward, positive and negative feedback control contributing to cancer progression. Besides its metabolic role, non-metabolic functions of PKM2 as protein kinase and transcriptional coactivator for c-MYC and hypoxia-inducible factor 1-alpha are essential for epidermal growth factor receptor activation-induced tumorigenesis. These biochemical activities are controlled by a shift in the oligomeric state of PKM2 that includes acetylation, oxidation, phosphorylation, prolyl hydroxylation and sumoylation. Metabolically active PKM2 tetramer is allosterically regulated and responds to nutritional and stress signals. Metabolically inactive PKM2 dimer is imported into the nucleus and can function as protein kinase stimulating transcription. A systems biology approach to PKM2 at the genome, transcriptome, proteome, metabolome and fluxome level reveals how differences in biomolecular structure translate into a global rewiring of cancer metabolism. Cancer systems biology takes us beyond the Warburg effect, opening unprecedented therapeutic opportunities.
authors: Systems Biology and Cancer Metabolism, Program for Quantitative and Systems Biology, University of California Merced, 5200 North Lake Road, Merced, CA 95343, USA.
authors: Fabian V
authors: FV
authors: Filipp
keywords: 6-bisphosphatase; 6-bisphosphate; Cancer metabolism; MYC; NMR; PKM1; PKM2; Warburg; catenin; control; epidermal growth factor receptor; feed-forward; feedback; fructose-1; glutamic-oxalacetic transaminase; glutaminase; hypoxia-inducible factor 1-alpha; isoform; metabolomics; omics; pyruvate dehydrogenase; pyruvate dehydrogenase kinase; pyruvate kinase; pyruvate kinase M2; serine; serine/arginine-rich splicing factor 3; seven in absentia homolog 2; signal transducer and activator of transcription 3; succinylaminoimidazolecarboxamide ribose-5-phosphate; systems biology
references: Proc Natl Acad Sci U S A. 2012 May 1;109(18):6904-9
references: 22509023
references: Science. 2002 Mar 1;295(5560):1662-4
references: 11872829
references: J Biochem. 1967 Jul;62(1):71-91
references: 4965281
references: Cell. 2012 Aug 17;150(4):685-96
references: 22901803
references: Mol Biosyst. 2013 Jun;9(6):1489-97
references: 23532321
references: Mol Cell. 2012 Dec 14;48(5):771-84
references: 23123196
references: Nature. 2008 Nov 27;456(7221):470-6
references: 18978772
references: Science. 2011 Dec 2;334(6060):1278-83
references: 22052977
references: Cell. 2011 May 27;145(5):732-44
references: 21620138
references: J Cell Biochem. 2009 May 15;107(2):293-302
references: 19308990
references: Pigment Cell Melanoma Res. 2012 Nov;25(6):732-9
references: 22846158
references: Mol Cell. 2012 Mar 9;45(5):598-609
references: 22306293
references: Biochem Biophys Res Commun. 1990 Mar 16;167(2):587-92
references: 2322244
references: Nature. 2008 Mar 13;452(7184):230-3
references: 18337823
references: Oncotarget. 2011 May;2(5):393-400
references: 21789790
references: Nat Struct Mol Biol. 2012 Feb 05;19(3):346-54
references: 22307054
references: Nature. 2008 Mar 13;452(7184):181-6
references: 18337815
references: Oncogene. 2012 Feb 9;31(6):683-93
references: 21725354
references: Nat Chem Biol. 2012 Oct;8(10):839-47
references: 22922757
references: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16713-8
references: 18946040
references: Nature. 2011 Dec 1;480(7375):118-22
references: 22056988
references: Nature. 2012 Nov 15;491(7424):458-462
references: 23064226
references: Anticancer Res. 2007 Nov-Dec;27(6B):3963-71
references: 18225557
references: Chem Biol. 2012 Sep 21;19(9):1187-98
references: 22999886
references: Nature. 2010 Jan 21;463(7279):364-8
references: 20010808
references: J Mol Cell Biol. 2012 Apr;4(2):79-87
references: 22044881
references: Anal Bioanal Chem. 2013 May;405(14):4937-43
references: 23508580
references: J Biol Chem. 2011 Dec 9;286(49):42626-42634
references: 21998308
references: Nat Cell Biol. 2012 Dec;14(12):1295-304
references: 23178880
references: Pigment Cell Melanoma Res. 2012 May;25(3):375-83
references: 22360810
references: Science. 2012 Nov 23;338(6110):1069-72
references: 23086999
references: Cancer Res. 2007 Feb 15;67(4):1602-8
references: 17308100
references: J Biol Chem. 2013 May 31;288(22):15971-9
references: 23576436
references: Exp Cell Res. 2009 Oct 1;315(16):2765-74
references: 19563799
references: Science. 2007 Apr 27;316(5824):550-1
references: 17463274
references: Mol Cell. 2011 Jun 24;42(6):719-30
references: 21700219