Pyruvate Carboxylase and Cancer Progression

Overview

Journal Cancer Metab

Publisher Biomed Central

Specialty Oncology

Date 2021 May 1

PMID 33931119

Citations 38

Authors

Violet A Kiesel

Madeline P Sheeley

Michael F Coleman

Eylem Kulkoyluoglu Cotul

Shawn S Donkin

Stephen D Hursting

Michael K Wendt

Dorothy Teegarden

Affiliations

Soon will be listed here.

Abstract

Pyruvate carboxylase (PC) is a mitochondrial enzyme that catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate (OAA), serving to replenish the tricarboxylic acid (TCA) cycle. In nonmalignant tissue, PC plays an essential role in controlling whole-body energetics through regulation of gluconeogenesis in the liver, synthesis of fatty acids in adipocytes, and insulin secretion in pancreatic β cells. In breast cancer, PC activity is linked to pulmonary metastasis, potentially by providing the ability to utilize glucose, fatty acids, and glutamine metabolism as needed under varying conditions as cells metastasize. PC enzymatic activity appears to be of particular importance in cancer cells that are unable to utilize glutamine for anaplerosis. Moreover, PC activity also plays a role in lipid metabolism and protection from oxidative stress in cancer cells. Thus, PC activity may be essential to link energy substrate utilization with cancer progression and to enable the metabolic flexibility necessary for cell resilience to changing and adverse conditions during the metastatic process.

Citing Articles

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References

Mackall J, Lane M . Role of pyruvate carboxylase in fatty acid synthesis: alterations during preadipocyte differentiation. Biochem Biophys Res Commun. 1977; 79(3):720-5. DOI: 10.1016/0006-291x(77)91171-8. View

Cheng T, Sudderth J, Yang C, Mullen A, Jin E, Mates J . Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc Natl Acad Sci U S A. 2011; 108(21):8674-9. PMC: 3102381. DOI: 10.1073/pnas.1016627108. View

Zeczycki T, St Maurice M, Attwood P . Inhibitors of Pyruvate Carboxylase. Open Enzym Inhib J. 2011; 3:8-26. PMC: 3238542. DOI: 10.2174/1874940201003010008. View

Pedersen K, Buckley R, Scioneaux R . Glucose induces expression of rat pyruvate carboxylase through a carbohydrate response element in the distal gene promoter. Biochem J. 2009; 426(2):159-70. DOI: 10.1042/BJ20091266. View

Warburg O, Wind F, Negelein E . THE METABOLISM OF TUMORS IN THE BODY. J Gen Physiol. 2009; 8(6):519-30. PMC: 2140820. DOI: 10.1085/jgp.8.6.519. View

Owen O, Kalhan S, Hanson R . The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem. 2002; 277(34):30409-12. DOI: 10.1074/jbc.R200006200. View

Cardaci S, Zheng L, Mackay G, van den Broek N, MacKenzie E, Nixon C . Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat Cell Biol. 2015; 17(10):1317-26. PMC: 4591470. DOI: 10.1038/ncb3233. View

DeBerardinis R, Cheng T . Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2009; 29(3):313-24. PMC: 2809806. DOI: 10.1038/onc.2009.358. View

Ma M, Zhang Y, Weng M, Wang S, Hu Y, Hou Z . Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase-Dependent Cell Proliferation in Gallbladder Cancer. Cancer Res. 2016; 76(18):5361-71. DOI: 10.1158/0008-5472.CAN-15-3047. View

10.

Timmerman L, Holton T, Yuneva M, Louie R, Padro M, Daemen A . Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell. 2013; 24(4):450-65. PMC: 3931310. DOI: 10.1016/j.ccr.2013.08.020. View

11.

Lee S, Jeon H, Ju M, Kim C, Yoon G, Han S . Wnt/Snail signaling regulates cytochrome C oxidase and glucose metabolism. Cancer Res. 2012; 72(14):3607-17. DOI: 10.1158/0008-5472.CAN-12-0006. View

12.

Bruntz R, Belshoff A, Zhang Y, Macedo J, Higashi R, Lane A . Inhibition of Anaplerotic Glutaminolysis Underlies Selenite Toxicity in Human Lung Cancer. Proteomics. 2019; 19(21-22):e1800486. PMC: 7153719. DOI: 10.1002/pmic.201800486. View

13.

Phannasil P, Ansari I, El Azzouny M, Longacre M, Rattanapornsompong K, Burant C . Mass spectrometry analysis shows the biosynthetic pathways supported by pyruvate carboxylase in highly invasive breast cancer cells. Biochim Biophys Acta Mol Basis Dis. 2016; 1863(2):537-551. PMC: 5243144. DOI: 10.1016/j.bbadis.2016.11.021. View

14.

Pavlova N, Thompson C . The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016; 23(1):27-47. PMC: 4715268. DOI: 10.1016/j.cmet.2015.12.006. View

15.

Morrot A, Fonseca L, Salustiano E, Gentile L, Conde L, Filardy A . Metabolic Symbiosis and Immunomodulation: How Tumor Cell-Derived Lactate May Disturb Innate and Adaptive Immune Responses. Front Oncol. 2018; 8:81. PMC: 5876249. DOI: 10.3389/fonc.2018.00081. View

16.

Reshef L, Hanson R, Ballard F . Glyceride-glycerol synthesis from pyruvate. Adaptive changes in phosphoenolpyruvate carboxykinase and pyruvate carboxylase in adipose tissue and liver. J Biol Chem. 1969; 244(8):1994-2001. View

17.

Salto R, Manzano M, Giron M, Cano A, Castro A, Vilchez J . A Slow-Digesting Carbohydrate Diet during Rat Pregnancy Protects Offspring from Non-Alcoholic Fatty Liver Disease Risk through the Modulation of the Carbohydrate-Response Element and Sterol Regulatory Element Binding Proteins. Nutrients. 2019; 11(4). PMC: 6521114. DOI: 10.3390/nu11040844. View

18.

Zhang Q, Koser S, Donkin S . Propionate induces mRNA expression of gluconeogenic genes in bovine calf hepatocytes. J Dairy Sci. 2016; 99(5):3908-3915. DOI: 10.3168/jds.2015-10312. View

19.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

20.

Jitrapakdee S, Wallace J . Structure, function and regulation of pyruvate carboxylase. Biochem J. 1999; 340 ( Pt 1):1-16. PMC: 1220216. DOI: 10.1042/bj3400001. View