Altered Metabolite Levels in Cancer: Implications for Tumour Biology and Cancer Therapy

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2016 Sep 24

PMID 27658530

Citations 166

Authors

Lucas B Sullivan

Dan Y Gui

Matthew G Vander Heiden

Affiliations

Soon will be listed here.

Abstract

Altered cell metabolism is a characteristic feature of many cancers. Aside from well-described changes in nutrient consumption and waste excretion, altered cancer cell metabolism also results in changes to intracellular metabolite concentrations. Increased levels of metabolites that result directly from genetic mutations and cancer-associated modifications in protein expression can promote cancer initiation and progression. Changes in the levels of specific metabolites, such as 2-hydroxyglutarate, fumarate, succinate, aspartate and reactive oxygen species, can result in altered cell signalling, enzyme activity and/or metabolic flux. In this Review, we discuss the mechanisms that lead to changes in metabolite concentrations in cancer cells, the consequences of these changes for the cells and how they might be exploited to improve cancer therapy.

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References

Spitz D, Sullivan S, Malcolm R, Roberts R . Glutathione dependent metabolism and detoxification of 4-hydroxy-2-nonenal. Free Radic Biol Med. 1991; 11(4):415-23. DOI: 10.1016/0891-5849(91)90159-z. View

Sullivan L, Chandel N . Mitochondrial reactive oxygen species and cancer. Cancer Metab. 2015; 2:17. PMC: 4323058. DOI: 10.1186/2049-3002-2-17. View

Suh Y, Arnold R, Lassegue B, Shi J, Xu X, Sorescu D . Cell transformation by the superoxide-generating oxidase Mox1. Nature. 1999; 401(6748):79-82. DOI: 10.1038/43459. View

Stine Z, Walton Z, Altman B, Hsieh A, Dang C . MYC, Metabolism, and Cancer. Cancer Discov. 2015; 5(10):1024-39. PMC: 4592441. DOI: 10.1158/2159-8290.CD-15-0507. View

Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C . An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013; 340(6132):626-30. PMC: 3985613. DOI: 10.1126/science.1236062. View

Mullen A, Hu Z, Shi X, Jiang L, Boroughs L, Kovacs Z . Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep. 2014; 7(5):1679-1690. PMC: 4057960. DOI: 10.1016/j.celrep.2014.04.037. View

Kung C, Hixon J, Choe S, Marks K, Gross S, Murphy E . Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem Biol. 2012; 19(9):1187-98. PMC: 3775715. DOI: 10.1016/j.chembiol.2012.07.021. View

Janeway K, Kim S, Lodish M, Nose V, Rustin P, Gaal J . Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 2010; 108(1):314-8. PMC: 3017134. DOI: 10.1073/pnas.1009199108. View

Kerr E, Gaude E, Turrell F, Frezza C, Martins C . Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature. 2016; 531(7592):110-3. PMC: 4780242. DOI: 10.1038/nature16967. View

10.

Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011; 19(1):17-30. PMC: 3229304. DOI: 10.1016/j.ccr.2010.12.014. View

11.

Santarius T, Bignell G, Greenman C, Widaa S, Chen L, Mahoney C . GLO1-A novel amplified gene in human cancer. Genes Chromosomes Cancer. 2010; 49(8):711-25. PMC: 3398139. DOI: 10.1002/gcc.20784. View

12.

Hamanaka R, Chandel N . Targeting glucose metabolism for cancer therapy. J Exp Med. 2012; 209(2):211-5. PMC: 3280882. DOI: 10.1084/jem.20120162. View

13.

Kaelin Jr W . Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases. Cold Spring Harb Symp Quant Biol. 2011; 76:335-45. PMC: 4197849. DOI: 10.1101/sqb.2011.76.010975. View

14.

Szatrowski T, Nathan C . Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991; 51(3):794-8. View

15.

Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M . Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res. 2013; 73(13):4158-68. DOI: 10.1158/0008-5472.CAN-12-4499. View

16.

WEINBERG A, MIZE C, WORTHEN H . The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. J Pediatr. 1976; 88(3):434-8. DOI: 10.1016/s0022-3476(76)80259-4. View

17.

Karihtala P, Kauppila S, Puistola U, Jukkola-Vuorinen A . Divergent behaviour of oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (HNE) in breast carcinogenesis. Histopathology. 2011; 58(6):854-62. DOI: 10.1111/j.1365-2559.2011.03835.x. View

18.

Marhenke S, Lamle J, Buitrago-Molina L, Canon J, Geffers R, Finegold M . Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development. Hepatology. 2008; 48(2):487-96. DOI: 10.1002/hep.22391. View

19.

Gerald D, Berra E, Frapart Y, Chan D, Giaccia A, Mansuy D . JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell. 2004; 118(6):781-94. DOI: 10.1016/j.cell.2004.08.025. View

20.

Tomlinson I, Alam N, Rowan A, Barclay E, Jaeger E, Kelsell D . Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002; 30(4):406-10. DOI: 10.1038/ng849. View