Cancer and Glucose Metabolism: A Review on Warburg Mechanisms
Keywords:
Cancer, Warburg effect, Metabolism, 2-deoxy-glucose, Therapeutic strategiesAbstract
Modification of all four major classes of macromolecules metabolism in cancer tissues is a common feature. This alteration is a requirement for rapid proliferation as it provides quick energy generation, enhanced macromolecule biosynthesis and maintenance of the redox state. In tumour cells, there is increased glucose metabolism to lactate in the presence of oxygen, a phenomenon known as the “Warburg effect”. Understanding the role of the Warburg effect in cancer progression and targeting this phenomenon as a possible target for cancer management has become paramount. Mechanisms such as acidification of tumour microenvironment, hypoxia-inducible factor (HIF) stabilisation, mutation of tumour suppressor genes and oncogenes, mitochondrial dysfunction, selected targeting by miRNA, altered glutamine metabolism and post-translational modifications have been found to induce the Warburg phenomenon. Other contributory mechanisms are isocitrate dehydrogenase gene mutation, mitochondria membrane transporters, and pyruvate dehydrogenase complex conditioning. Chemical compounds such as 2-deoxy-glucose, 3-bromopyruvate and dichloroacetic acid target this phenomenon to reverse altered metabolism. A better holistic understanding of these mechanisms will help uncover novel metabolism-based therapeutic strategies that may play a role in halting the Warburg effect and ultimately, cancer progression.
References
Matthews HK, Bertoli C, de Bruin RA. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022; 23(1):74-88.
Xia C, Dong X, Li H, Cao M, Sun D, He S, Yang F, Yan X, Zhang S, Li N, Chen W. Cancer statistics in China and United States, 2022: Profiles, trends, and determinants. Chin Med J. 2022; 135(5):584-590.
Martínez-Reyes I and Chandel NS. Cancer metabolism: looking forward. Nat Rev Cancer. 2021; 21(10):669-680.
Cairns RA, Harris I, McCracken S, Mak TW. Cancer cell metabolism. Cold Spring Harb. Symp. Quant Biol. 2011; 76:299-311.
Cairns R, Harris I, Mak T. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011; 11:85-95.
Rotimi SO, Rotimi OA, Salako A, Jibrin P, Oyelade J, Iweala E. Gene expression profiling analysis reveals putative phytochemotherapeutic target for castrationresistant prostate cancer. Front Oncol. 2019; 9:714.
Yakubu OF, Adebayo AH, Dokunmu TM, Zhang YJ, Iweala EE. Cytotoxic effects of compounds isolated from Ricinodendron heudelotii. Molecules. 2019; 24(1):145.
Warburg O. On the origin of cancer cells. Sci. 1956; 123:309-314.
Bensinger S and Christofk H. New aspects of the Warburg effect in cancer cell biology. Semin. Cell Dev Biol. 2012; 23:352-361.
Pedersen PL. Warburg, me and Hexokinase 2: multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr. 2007; 39:211-222.
Demetrius LA, Coy JF, Tuszynski JA. Cancer proliferation and therapy: the Warburg effect and quantum metabolism. Theor Biol Med Model. 2010; 7:2.
Lopez-Lazaro M. The Warbur Effect: Why and how do cancer cells activate glycolysis inthe presence of oxygen? Anti-Cancer Agents Med Chem. 2008; 8(3):305-312.
Lunt SY, Van der Heiden MG. Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011; 27:441–464.
Berg J, Tymoczko J, Stryer L. Biochemistry. New York: W.H Freeman and Co.; 2002. 671 p.
Upadhyay M, Samal J, Kandpal M, Singh O, Vivekanandan P. The Warburg effect: Insights from the past decade. Pharmacol Ther. 2013; 137:318-330.
Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1-alpha-dependent mechanism. J Biol Chem. 2006; 281:9030–9037.
Gatenby RA and Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004; 4:891-899.
Schornack PA and Gillies RJ. Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors. Neoplasia. 2003; 5:135-145.
Nijsten MW and van Dam GM. Hypothesis: using the Warburg effect against cancer by reducing glucose and providing lactate. Med. Hypotheses. 2009; 73:48-51.
Gillies RJ, Robey I, Gatenby RA. Causes and consequences of increased glucose metabolism of cancers. J Nucl Med. 2008; 49(Suppl. 2):24S-42S.
Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3:177-185.
Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006; 3:187-197.
Semenza GL. HIF-1: Upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010; 20:51-56.24. Koike T, Kimura N, Miyazaki K, Yabuta T, Kumamoto K, Takenoshita S, Chen J, Kobayashi M, Hosokawa M, Taniguchi A, Kojima T. Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates. Proc Natl Acad Sci. 2004; 101:8132-8137.
Ferreira IG, Carrascal M, Mineiro AG, Bugalho A, Borralho P, Silva Z, Dall'olio F, Videira PA. Carcinoembryonic antigen is a sialyl Lewis x/a carrier and an E‑selectin ligand in non‑small cell lung cancer. Int J Oncol. 2019; 55(5):1033-1048.
Kim J and Dang C. Cancer’s molecular sweet tooth and the Warburg Effect. Cancer Res. 2006; 66:8927-8930.
Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 2008; 15:521-529.
Rahl PB and Young RA. MYC and transcription elongation. Cold Spring Harb. Perspect Med. 2014; 4(1):a020990.
Aughey GN, Grice SJ, Liu JL. The interplay between Myc and CTP synthase in Drosophila. PLoS Genet. 2016; 12(1):e1005867.
Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, Diaz Jr LA. Glucose deprivation contributes to the development of KRAS pathway. Sci. 2009; 325:1555-1559.
Guntuku L, Naidu V, Yerra V. Mitochondrial dysfunction in gliomas: Pharmacotherapeutic potential of natural compounds. Curr Neuropharmacol. 2016; 14:567-583.
Gottlieb E and Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer. 2005; 5:857-866.
Ayyasamy V, Owens KM, Desouki MM, Liang P, Bakin A, Thangaraj K, Buchsbaum DJ, LoBuglio AF, Singh KK. Cellular model of Warburg effect identifies tumor promoting function of UCP2 in breast cancer and its suppression by genipin. PLoS One. 2011; 6:e24792.
Samudio I, Fiegl M, Andreeff M. Mitochondrial uncoupling and the Warburg effect: Molecular basis for the reprogramming of cancer cell metabolism. Cancer Res. 2009; 69:2163-2166.
Samudio I, Fiegl M, McQueen T, Clise-Dwyer K, Andreeff M. The Warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. Cancer Res. 2008; 68:5198-5205.
Gogvadze V, Zhivotovsky B, Orrenius S. The Warburg effect and mitochondrial stability in cancer cells. Mol Asp Med. 2010; 31:60-74.
Setlai BP, Hull R, Reis RM, Agbor C, Ambele MA, Mulaudzi TV, Dlamini Z. MicroRNA interrelated epithelial mesenchymal transition (EMT) in blioblastoma. Genes. 2022; 13(2):224.
Hatziapostolou M, Polytarchou C, Iliopoulos D. miRNAs link metabolic reprogramming. Trends Endocrinol. Metab. 2013; 24:361-373.
Li H and Chen W. Role of microRNAs in the Warburg effect and mitochondrial metabolism in cancer. Asian Pac J Cancer Prev. 2014; 15:7015-7019.
Mazurek S, Boschek CB, Hugo F, Eigenbrodt E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol. 2005; 15:300-308.
Asgari Y, Zabihinpour Z, Salehzadeh-Yazdi A, Schreiber F, Masoudi-Nejad A. Alterations in cancer cell metabolism: The Warburg effect and metabolic adaptation. Genomics. 2015; 105(5-6):275-281.
Hitosugi T, Kang S, Van der Heiden MG, Chung TW, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, Chen GZ, Xie J. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal. 2009; 2(97):ra73.
Robey R and Hay N. Is Akt the Warburg kinase? – Aktenergy metabolism interactions and oncogenesis. Semin. Cancer Biol. 2009; 19:25-31.
Anastasiou D, Poulogiannis G, Asara J, Boxer M, Jiang J, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to antioxidant responses. Sci. 2011; 334:1278–1283.
Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, Zha Z, Liu Y, Li ZI, Xu Y, Wang G. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone- mediated autophagy and promotes tumor growth. Mol Cell. 2011; 42(6):719-730.
Wu W and Zhao S. Metabolic changes in cancer: Beyond the Warburg effect. Acta Biochim Biophys Sin. 2013; 45:18-26.
Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 2016; 27(4):599-608.
Olayanju B, Hampsey J, Hampsey M. Genetic analysis of the Warburg effect in yeast. Adv Biol Regul. 2015; 57:185-192.
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S, Ito S, Yang C, Wang P, Xiao MT, Liu LX. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alphaketoglutarate-dependent dioxygenases. Cancer Cell. 2011; 19(1):17-30.
Devic S. Warburg Effect-a consequence or the cause of carcinogenesis? J Cancer. 2016; 7:817-822.
Pladys A, Couchoud C, LeGuillou A, Siebert M, Vigneau C, Bayat S. Type 1 and Type 2 diabetes and cancer mortality in the 2002-2009 cohort of 39 811 French dialyzed patients. PLoS One. 2015; 10:e0125089.
Rebecca L, Kimberly D, Ahmedin J. Cancer statistics 2015. CA: Cancer J Clin. 2015; 65:5-29.
Shelton N and Mindell J. Epidemiological evidence of a relationship between type-1 diabetes mellitus and cancer: A review of the existing literature. Int J Cancer. 2013; 132:501-508.
Maldonado EN and Lemasters J. ATP/ADP ratio, the missed connection between mitochondria and the Warburg effect. Mitochondrion. 2014; 19:78-84.
Holmuhamedov E, Czerny C, Beeson C, Lemasters J. Ethanol suppresses ureagenesis in rat hepatocytes: Role of acetaldehyde. J Biol Chem. 2012;287:7692-7700.
Lemasters J, Holmuhamedov E, Czerny C, Zhong Z, Maldonado E. Regulation of mitochondrial function by voltage dependent anion channels in ethanol metabolism and the Warburg effect. Biochim Biophys Acta Mol Basis Dis. 2012; 1818:1536-1544.
Palmieri F. The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Asp Med. 2013; 34:465–484.
Maldonado E, DeHart D, Patnaik J, Klatt S, Beck-Gooz M, Lemasters J. ATP/ADP turnover and import of glycolytic atp into mitochondria in cancer cells is independent of the adenine nucleotide translocator. J Biol Chem. 2016; 291:jbc-M116.
Maldonado EN, Vuicich J, DeHart DN, Rodebaugh HS, Lemasters JJ. Translocation of glycolytic ATP into mitochondria of cancer cells does not utilise the adenine nucleotide transporter. Biophys J. 2013; 104:303a–304a.
Vinaik R, Barayan D, Auger C, Abdullahi A, Jeschke MG. Regulation of glycolysis and the Warburg effect in wound healing. JCI Insight. 2020; 5(17):e138949.
Tran Q, Lee H, Park J, Kim S, Park J. Targeting cancer metabolism - Revisiting the Warburg effects. Toxicol Res. 2016; 32:177-193.
Wang XX, Yin GQ, Zhang ZH, Rong ZH, Wang ZY, Du DD, Wang YD, Gao RX, Xian GZ. TWIST1 transcriptionally regulates glycolytic genes to promote the Warburg metabolism in pancreatic cancer. Exp Cell Res. 2020; 386(1):111713.
Urakami K, Zangiacomi V, Yamaguchi K, Kusuhara M. Impact of 2-deoxy-D-glucose on the target metabolome profile of a human endometrial cancer cell line. Biomed Res. 2013; 34:221-229.
Golding JP, Wardhaugh T, Patrick L, Turner M, Phillips JB, Bruce JI, Kimani SG. Targeting tumour energy metabolism potentiates the cytotoxicity of 5-aminolevulinic acid photodynamic therapy. Br. J. Cancer. 2013;109:976-82.
Zhou L, Liu L, Chai W, Zhao T, Jin X, Guo X, Han L, Yuan C. Dichloroacetic acid upregulates apoptosis of ovarian cancer cells by regulating mitochondrial function. OncoTargets Ther. 2019; 12:1729.
Hu HJ, Zhang C, Tang ZH, Qu SL, Jiang ZS. Regulating the Warburg effect on metabolic stress and myocardial fibrosis remodeling and atrial intracardiac waveform activity induced by atrial fibrillation. Biochem. Biophys. Res. Commun. 2019; 516(3):653-660.
Rai Y, Yadav P, Kumari N, Kalra N, Bhatt AN. Hexokinase II inhibition by 3-bromopyruvate sensitises myeloid leukemic cells K-562 to anti-leukemic drug, daunorubicin. Biosci Rep. 2019; 39(9):BSR20190880.
Fan T, Sun G, Sun X, Zhao L, Zhong R, Peng Y. Tumor energy metabolism and potential of 3-bromopyruvate as an inhibitor of aerobic glycolysis: Implications in tumor treatment. Cancers. 2019; 11(3):317.
Pulaski L, Jatczak-Pawlik I, Sobalska-Kwapis M, Strapagiel D, Bartosz G, Sadowska-Bartosz I. 3-Bromopyruvate induces expression of antioxidant genes. Free Radic Res. 2019; 53(2):170-178.
Tyagi K, Mandal S, Roy A. Recent advancements in therapeutic targeting of the Warburg effect in refractory ovarian cancer: a promise towards disease remission. Biochim Biophys Acta - Rev Cancer. 2022; 1876(1):188563.
Li J, Qu P, Zhou XZ, Ji YX, Yuan S, Liu SP, Liu SP, Zhang QG. Pimozide inhibits the growth of breast cancer cells by alleviating the Warburg effect through the P53 signaling pathway. Biomed Pharmacother. 2022; 150:113063
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