Please read the attached article and summarize your understanding of it. The summary of should be between 700-1000 words but if you write more it will not count against you.
Please read the attached article and summarize your understanding of it. The summary of should be between 700-1000 words but if you write more it will not count against you. This review article is a
Mini-review on Glycolysis and Cancer M. Akram Published online: 1 June 2013 # Springer Science+Business Media New York 2013 AbstractGlycolysis is a universal pathway in the living cells. The complete pathway of glycolysis was elucidated in 1940. This pathway is often referred to as Embden–Meyer- hof pathway in honor of the two biochemists that made a major contribution to the knowledge of glycolysis. The objective of the study was to review the published literature on glycolysis and relation to cancer. The material for this review was taken mostly from up-to-date biochemistry text- books and electronic journals. To collect publications, PubMed and the Cochrane database of systematic reviews were used. Some other relevant references were collected from personal database of papers on glycolysis and cancer. Several glycolytic inhibitors are currently in preclinical and clinical development. Inhibition of glycolysis in cancer cells is a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. This article is an important topic to be considered by cancer researchers and those who treat cancers. KeywordsGlycolysis. Cancer. Research study. Literature review Introduction Glycolysis takes place in all cells of the body. The enzymes of this pathway are present in the cytosomal fraction of the cell. Glycolysis occurs in the absence of oxygen (anaerobic) or in the presence of oxygen (aerobic). Lactate is the endproduct under anaerobic condition. In the aerobic condition, pyruvate is formed, which is then oxidized to CO 2and H 2O . Glycolysis is a major pathway for ATP synthesis in tissues lacking mitochondria, e.g., erythrocytes, cornea and lens. Glycolysis is very essential for brain which is dependent on glucose for energy. The glucose in brain has to undergo glycolysis before it is oxidized to CO 2and H 2O. Glycolysis is a central metabolic pathway with many of its intermediates providing branch point to other pathways. Thus, the interme- diates of glycolysis are useful for the synthesis of amino acids and fat. Reversal of glycolysis along with the alternate ar- rangements at the irreversible steps will result in the synthesis of glucose (gluconeogenesis). Glycolysis rate is 200 times higher in tumor cells than the normal cells. Otto Warburg has described this phenomenon in 1930; this is why now it is called as the Warburg effect. According to this phenome- non, dysfunctionality in mitochondrial metabolism is primar- ily cause of cancer, rather than because of uncontrolled growth of cells. Warburg effect has been explained by various theo- ries. One theory is that an increase in glycolysis rate is favor- able to the body. Enzymes of Glycolysis The enzymes involved in glycolysis are hexokinase, phosphoglucoisomerase, phosphofructokinase, aldolase, tri- ose phosphate isomerase, glyceraldehyde-3-phosphate de- hydrogenase, phosphoglycerate kinase, phosphoglycerate mutase, enolase and pyruvate kinase. Reactions of Glycolysis The pathway can be divided into three distinct phases: 1.Energy investment phase or priming phase M. Akram (*) Department of Eastern Medicine and Surgery, Faculty of Medical and Health Sciences, The University of Poonch, Azad Jammu and Kashmir, Pakistan e-mail: [email protected] M. Akram e-mail: [email protected] J Canc Educ (2013) 28:454–457 DOI 10.1007/s13187-013-0486-9 2.Splitting phase 3.Energy-generation phase Energy Investment Phase Glucose is phosphorylated to glucose 6-phosphate by hexo- kinase or glucokinase. This is an irreversible reaction de- pendent on ATP and Mg 2+. The hexokinase enzyme is present in almost all the tissues. It catalyzes phosphorylation of various hexoses (fructose, mannose, etc.). It has low Km for substrates (approximately 0.1 Mm) and inhibited by glucose 6-phosphate . Products of Glycolysis Glycolysis produces a net amount of two ATPs and two NADHs. Splitting Phase Six carbon fructose 1,6-diphosphate is divided into two three-carbon compounds, glyceraldehyde-3-phosphate and dihydroxyacetone phosphate by aldolase enzyme. The enzyme phosphotriose isomerase catalyzes the reversible interconversion of glyceraldehydes 3-phosphate and di- hydroxyacetone phosphate. Thus, two molecules of glyceraldehydes 3-phosphate are formed from one mol- ecule of glucose Energy-Generation Phase Glyceraldehyde 3-phosphate dehydrogenase converts glycer- aldehyde 3-phosphate to 1,3-bisphosphoglycerate. This step is important, as it is involved in the formation of NADH 2and high-energy compound 1,3-bisphosphoglycerate. In aerobic conditions, NADH passes through the electron transport chain and six ATPs (2 × 3 ATPs) are synthesized by oxidative phosphorylation. The enzyme phosphoglycerate kinase acts on 1,3-bisphoglycerate resulting in the synthesis of ATP and the formation of 3-phosphoglycerate. This step is a good example of substrate level phosphorylation, be- cause ATP is synthesized from the substrate without the participation of the electron transport chain. Phosphoglyc- erate kinase reaction is reversible, a rare example among the kinase reaction. 3-Phosphoglycerate is converted to 2-phosphoglycerate by phosphosphoglycerate mutase. This isomerization is a reaction. The high-energy phosphoenol pyruvate compound is produced by 2-phosphoglycerate by the enzyme enolase . This enzyme requires magnesium and manganese, and it inhibited by fluoride. For the estimation of glucose in the blood in the labora- tory, fluoride is added to blood to prevent glycolysis by cellsso that glucose in the blood is properly assessed. The pyru- vate kinase enzyme catalyzes the transfer of high-energy phosphate from phosphoenol pyruvate to ADP, leading to the formation of ATP. This step is also a substrate level phosphorylation. This reaction is irreversible. Conversion of Pyruvate to Lactate—Significance The fate of pyruvate produced in glycolysis depends on the presence or absence of oxygen to the cells. Under anaerobic conditions (lack of O2), pyruvate is reduced by NADH to lactate in the presence of the enzyme lactate dehydrogenase . The NADH 2used in this step is taken from the reaction catalyzed by glyceraldehydes 3-phosphate dehydrogenase. The formation of lactate allows the regeneration of NAD +that can be reused by glyceraldehyde 3-phosphate dehydrogenase, so that glycolysis proceeds even in the absence of oxygen supply ATP. The occurrence of uninterrupted glycolysis is very essential in skeletal muscle during strenuous exercise where oxygen supply is very limited. Glycolysis in the eryth- rocytes leads to lactate production, since mitochondria—the centers for aerobic oxidation—are absent. Brain, retina, skin, renal medulla, and gastrointestinal tract derive most of their energy from glycolysis . Production of ATP in Glycolysis Two ATPs are synthesized in anaerobic glycolysis, while eight ATPs are synthesized under aerobic conditions. When glycolysis is from glycogen, more ATPs are produced. This is because no ATP is consumed for activation of glucose (glycogen directly produces glucose 1-phosphate forming glucose 6-phosphate). Thus, in anaerobic glycolysis, three ATPs are produced from glycogen . Glycolysis and Shuttle Pathway In the presence of mitochondria and oxygen, the NADH produced in glycolysis may be involved in the shuttle routes for the synthesis of ATP. If cytosolic NADH use malate aspartate shuttle, three ATPs are produced from each mole- cule of NADH. This contrasts with glycerol phosphate shuttle which produces only two ATPs . Cancer and Glycolysis Cancer cells display increased uptake of glucose and gly- colysis. As the tumors grow rapidly, the blood vessels are thus in a condition of hypoxia . Due to this, anaerobic J Canc Educ (2013) 28:454–457455 glycolysis predominantly occurs to supply energy. The can- cer cells get adapted of hypoxic glycolysis through the involvement of a transcription factor namely hypoxia- inducible transcription factor (HIF) . HIF increases the synthesis of glycolytic enzymes and the glucose trans- porters. However, the cancer cells cannot grow and survive without proper vascularization. One of the modalities of cancer treatment is to use drugs that can inhibit vasculari- zation of tumors . Sun et al. have reported that reversal of the glycolytic phenotype by dichloroacetate inhibits met- astatic breast cancer cell growth in vitro and in vivo . Xu et al. have reported the inhibition of glycolysis in cancer cells that is a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypox- ia . Altenberg et al. have reported that genes of glycol- ysis are ubiquitously overexpressed in 24 cancer classes . Broadley et al. have reported that novel phloroglucinol PMT7 kills glycolytic cancer cells by blocking autophagy and sensitizing to nutrient stress . Fantin et al. have reported that attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tu- mor maintenance . Ha et al. have reported that Caveolin- 1 increases aerobic glycolysis in colorectal cancers by stim- ulating HMGA1-mediated GLUT3 transcription . Scatena et al. have reported the glycolytic enzyme inhibitors in cancer treatment . Fang et al. have reported that MicroRNA-143 (miR-143) regulates cancer glycolysis via targeting hexokinase 2 gene . Granchi et al. have report- ed the anticancer agents that counteract tumor glycolysis . Sukhatme et al. have reported that glycolytic cancer cells lacking 6-phosphogluconate dehydrogenase metabo- lize glucose to induce senescence . Wang and his col- leagues stated that IDH1 affinity for ICT is reduced by mutations at sites A132Arg, A109Arg, and B212Lys IDH1 affinity for ICT is increased by mutation at sites A77Thr, A94Ser, and A275Asp, that enhances IDN1 catalytic activ- ity. Mutant IDH1 proteins with higher catalytic activity is a novel therapy useful for glioblastoma multiforme . We are discussing about anaerobic glycolysis and its effect on cancer. In case of anaerobic glycolysis, lactic acid is pro- duced. Alternate source of energy are lipids and proteins but their oxidation occurs in mitochondria that is totally oxida- tive pathway. Therefore, in case of anaerobic conditions, TCA does not work properly for oxidation of lipids and proteins. Cancer cells mostly depend on glycolysis for ATP production due to mitochondrial injury and hypoxia. Inhi- bition of glycolysis severely depletes ATP production in cancer cell with mitochondrial respiration defects. As a result, there will be dephosphorylation of glycolysis–apo- ptosis integrating molecule BAD at Ser(112), relocalization of BAX to mitochondria, and massive cell death. Xu and his colleagues stated that glycolysis inhibition kills colon cancer cells and lymphoma cells in anaerobic conditions. ATPdepletion via glycolysis pathway inhibits potently induced apoptosis in multidrug-resistant cells which indicates that depletion of cellular energy is an effective way to treat multidrug resistance. The study of Xu and his colleagues indicated that glycolysis inhibition is useful in cancer ther- apy and also overcome the drug resistance . Irreversible Steps in Glycolysis Most of the reactions of glycolysis are reversible. However, the three steps catalyzed by the enzymes hexokinase (or glucokinase), phosphofructokinase, and pyruvate kinase are irreversible. These three stages mainly regulate glycoly- sis. The reversal of glycolysis, with alternate arrangements made at the three irreversible stages, leads to the synthesis of glucose from pyruvate (gluconeogenesis) . Regulation of Glycolysis Enzyme Activator The three enzymes, namely hexokinase (and glucokinase), phosphofructokinase, and pyruvate kinase, catalyze the ir- reversible reaction regulate glycolysis. Hexokinase is acti- vated by AMP/ADP. Phosphofructokinase is activated by AMP/ADP and fructose-2,6-bisphosphate. Pyruvate kinase is activated by AMP/ADP and fructose-1,6-bisphosphate [23,24]. Enzyme Inhibitor Hexokinase is inhibited by glucose-6-phosphate. Phospho- fructokinase is inhibited by ATP and citrate. Pyruvate kinase is inhibited by ATP, acetyl CoA, and alanine. Significance of 2,3-BPG Production of 2,3-bisphosphoglycerate (BPG) allows the glycolysis to proceed without the synthesis of ATP. This is advantageous to erythrocytes since glycolysis occurs when the need for ATP is minimal. Rapoport–Leubering cycle is, therefore, regarded as a shunt pathway of glycolysis to dissipate or waste the energy not needed by erythrocytes. 2,3-BPG, however, is not a waste molecule in RBC. It combines with hemoglobin (Hb) and reduced Hb affinity with oxygen. Therefore, in the presence of 2,3-BPG, oxy- hemoglobin unloads more oxygen to the tissues. Increase in erythrocyte 2,3-BPG is observed in hypoxic condition, high altitude, fetal tissues, anemic conditions, etc. In all these cases, 2,3-BPG will enhance the supply of oxygen to the tissues. Glycolysis in the erythrocytes is linked with 2,3- 456J Canc Educ (2013) 28:454–457 BPG production and oxygen transport. In the deficiency of the enzyme hexokinase, glucose is not phosphorylated, hence the synthesis and concentration of 2,3-BPG are low in RBC. The hemoglobin exhibits high oxygen affinity in hexokinase-defective patients. On the other hand, the level of 2,3-BPG in erythrocytes is high in patients with pyruvate kinase deficiency, resulting in low oxygen affinity . Conclusion Glycolysis is a universal pathway in the living cells. The complete pathway of glycolysis was elucidated in 1940. This pathway is often referred to as Embden–Meyerhof pathway in honor of the two biochemists that made a major contribution to the knowledge of glycolysis. This article is an important topic to be considered by cancer researchers and those who treat cancers. This is a very important subject that has been addressed. References 1. Bacci G, Capanna R, Orlandi M (1985) Prognostic significance of serum lactic acid dehydrogenase in Ewing’s tumor of bone. Ric Clin Lab 15:89–96 2. Veramendi J, Fernie AR, Leisse A, Willmitzer L, Trethewey RN (2002) Potato hexokinase 2 complements transgenic Arabidopsis plants deficient in hexokinase 1 but does not play a key role in tuber carbohydrate metabolism. Plant Mol Biol 49:491–501 3. Tang GQ, Hardin SC, Dewey R, Huber SC (2003) A novel C- terminal proteolytic processing of cytosolic pyruvate kinase, its phosphorylation and degradation by the proteasome in developing soybean seeds. Plant J 34:77–93 4. Goldblatt H, Cameron C (1953) Induced malignancy in cells from rat myocardium subjected to intermittent anaerobiosis during long propagation in vitro. J Exp Med 97:525–552 5. Druml W, Kleinberger G, Neumann E, Pichler M, Gassner A (1981) [Acute leukemia associated with lactic acidosis] [article in German]. Schweiz Med. Wochenschr 111:146–150 6. Allard MF, Schönekess BO, Henning SL, English DR, Lopaschuk GD (2008) Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol 267(2):742–750 7. Pérez-Rodríguez J, Sánchez-Jiménez F, Márquez FJ, Medina MA, Quesada AR, Núñez de Castro I (1987) Malate-citrate cycle during glycolysis and glutaminolysis in Ehrlich ascites tumor cells. Biochimie 69(5):469–474 8. Warburg O (1910) The metabolism of tumours. J Physiol Chem 56:66–3059. Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277:23111–23115 10. Schwickert G, Walenta S, Sundfør K, Rofstad EK, Mueller-Klieser W (1995) Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res 55:4757–4759 11. Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC (2009) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120(1):253–260 12. Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, Keating MJ, Huang P (2005) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 65(2):613–621 13. Altenberg B, Greulich KO (2008) Genes of glycolysis are ubiquitous- ly overexpressed in 24 cancer classes. Genomics 84(6):1014–1020 14. Broadley K, Larsen L, Herst PM, Smith RA, Berridge MV, McConnell MJ (2011) The novel phloroglucinol PMT7 kills gly- colytic cancer cells by blocking autophagy and sensitizing to nutrient stress. J Cell Biochem 112(7):1869–1879 15. Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9(6):425–434 16. Ha TK, Her NG, Lee MG, Ryu BK, Lee JH, Han J, Jeong SI, Kang MJ, Kim NH, Kim HJ, Chi SG (2012) Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1- mediated GLUT3 transcription. Cancer Res 72(16):4097–4109 17. Scatena R, Bottoni P, Pontoglio A, Mastrototaro L, Giardina B (2002) Glycolytic enzyme inhibitors in cancer treatment. Expert Opin Investig Drugs 17(10):1533–1545 18. Fang R, Xiao T, Fang Z, Sun Y, Li F, Gao Y, Feng Y, Li L, Wang Y, Liu X, Chen H, Liu XY, Ji H (2012) MicroRNA-143 (miR-143) regulates cancer glycolysis via targeting hexokinase 2 gene. J Biol Chem 287(27):23227–2335 19. Granchi C, Minutolo F (2012) Anticancer agents that counteract tumor glycolysis. ChemMedChem 7(8):1318–1350 20. Sukhatme VP, Chan B (2012) Glycolytic cancer cells lacking 6- phosphogluconate dehydrogenase metabolize glucose to induce senescence. FEBS Lett 586(16):2389–2395 21. Wang MD, Shi YF, Wang H, Wang JL, Ma WB, Wang RZ. Virtual mutagenesis of isocitrate dehydrogenase 1 involved in glioblasto- ma multiforme. Chin Med J 124(17):2611–2615) 22. Koebmann BJ, Westerhoff HV, Snoep JL, Nilsson D, Jensen PR (2002) The glycolytic flux inEscherichia coliis controlled by the demand for ATP. J Bacteriol 184:3909–3916 23. Guyton A, Hall J (1996) Textbook of medical physiology, 9th edn. W.B. Saunders, Philadelphia, PA, pp 868–870 24. Fernie AR, Roscher A, Ratcliffe RG, Kruger NJ (2011) Fructose 2,6-bisphosphate activates pyrophosphate: fructose 6-phosphate 1- phosphotransferase and increases triose phosphate to hexose phos- phate cycling in heterotrophic cells. Planta 212:250–263 25. Mulquiney PJ, Bubb WA, Kuchel PW. Model of 2,3- bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: in vivo kinetic characteriza- tion of 2,3-bisphosphoglycerate synthase/phosphatase using 13C and 31P NMR. Biochem J 342 (3):567–580 J Canc Educ (2013) 28:454–457457