Glucose is an essential source of energy for mammalian cells with the end product of glycolysis being pyruvate. For every molecule of glucose, two molecules of pyruvate are produced, while two molecules of adenosine diphosphate (ADP) are converted into adenosine triphosphate (ATP) and two molecules of NAD+ transformed into NADH (dihydronicotinamide adenine dinucleotide). This step does not depend on the presence of oxygen. Pyruvate is subsequently used for further energy production.
The fate of pyruvate is dependent on the presence of oxygen. Under aerobic conditions pyruvate enters into the mitochondria for oxidation. At these organelles, the carbon atoms of the acetyl groups are liberated, via the Krebs (citric acid) cycle, as carbon dioxide, while the hydrogen atoms are transferred to the NAD+ which, in turn, is reduced to NADH. The NADH electrons are subsequently transported into a series of molecules forming the electron-transport chain, transferring their energy to ATP, the main source of cellular energy. Finally, electrons and protons are combined with oxygen to produce water. This pathway results in the largest possible number of ATP molecules, i.e., energy, that can be obtained from pyruvate.
Keywords
- Colorectal Cancer
- Lactate Dehydrogenase
- Metastatic Colorectal Cancer
- Colorectal Adenocarcinoma
- Community Clinical Oncology Program
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References
Aebersold, D.M., Burri, P., Beer, K.T., Laissue, J., Djonov, V., Greiner, R.H., and Semenza, G.L. 2001. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer.Cancer Res.61:2911–2916.
Aft, R.L., Zhang, F.W., and Gius, D. 2002. Evaluation of 2-deoxy-D-glucose as a chemo-therapeutic agent: mechanism of cell death.Br. J. Cancer 87:805–812.
Akakura, N., Kobayashi, M., Horiuchi, I., Suzuki, A., Wang, J., Chen, J., Niizeki, H., Kawamura, K., Hosokawa, M., and Asaka, M. 2001. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apop-tosis induced by hypoxia and nutrient deprivation.Cancer Res.61:6548–6554.
Belozerov, V.E., and Van Meir, E.G. 2006. Inhibitors of hypoxia-inducible factor-1 signaling.Curr. Opin. Investig. Drugs 7:1067–1076.
Bronk, S.F., and Gores, G.J. 1991. Acidosis protects against lethal oxidative injury of liver sinusoidal endothelial cells.Hepatology 14:150–157.
Brown, J.M. 2002. Tumor microenvironment and the response to anticancer therapy.Cancer. Biol. Ther. 1:453–458.
Diaz, R., Aparicio, J., Girones, R., Molina, J., Palomar, L., Segura, A., and Montalar, J. 2005. Analysis of prognostic factors and applicability of Kohne's prognostic groups in patients with metastatic colorectal cancer treated with first-line irinotecan or oxaliplatin-based chemotherapy.Clin. Colorect. Cancer 5:197–202.
Ebert, B.L., and Bunn, H.F. 1998. Regulation of transcription by hypoxia requires a multipro-tein complex that includes hypoxia-inducible factor 1, an adjacent transcription factor, and p300/CREB binding protein.Mol. Cell. Biol.18:4089–4096.
Elstrom, R.L., Bauer, D.E., Buzzai, M., Karnauskas, R., Harris, M.H., Plas, D.R., Zhuang, H., Cinalli, R.M., Alavi, A., Rudin, C.M., and Thompson, C.B. 2004. Akt stimulates aerobic glycolysis in cancer cells.Cancer Res.64:3892–3899.
Firth, J.D., Ebert, B.L., and Ratcliffe, P.J. 1995. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and CAMP response elements.J. Biol. Chem. 270:2102–2107.
Fountzilas, G., Gossios, K., Zisiadis, A., Svarna, E., Skarlos, D., and Pavlidis, N. 1996. Prognostic variable in patients with advanced colorectal cancer treated with fluorouracil and leucov-orin-based chemotherapy.Med. Pediatr. Oncol.26:305–317.
Giatromanolaki, A., and Harris, A.L. 2001. Tumour hypoxia, hypoxia signaling pathways and hypoxia inducible factor expression in human cancer.Anticancer Res.21:4317–4324.
Gray, L.H., Conger, A.S.D., Ebert, M., Hornsey, S., and Scott, O.C.A. 1953. The concentration of oxygen dissolved in tissue at the time of irradiation as a factor in radiotherapy.Br. J. Radial.26:638–648.
Griffini, P., Freitas, I., Vigorelli, E., and Van Noorden, C.J. 1994. Changes in the zonation of lactate dehydrogenase activity in lobules of rat liver after experimentally induced colon carcinoma metas-tases.Anticancer Res.14:2537–2540.
Gupta, D., Lammersfeld, C.A., Vashi, P.G., Burrows, J., Lis, C.G., and Grutsch, J.F. 2005. Prognostic significance of Subjective Global Assessment (SGA) in advanced colorectal cancer.Eur. J. Clin. Nutr.59:35–40.
Halestrap, A.P., and Price, N.T. 1999. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation.Biochem. J. 2:281–299.
Harris, A.L. 2002. Hypoxia: a key regulatory factor in tumour growth.Nat. Rev.Cancer 2:38–47.
Hecht, J.R., Trarbach, T., Jaeger, E., Hainsworth, J., Wolff, R., Lloyd, K., BodokGy, G., Borner, M., Laurent, D., and Jacques, C. 2005. A randomized, double-blind, placebo-controlled, phase III study in patients (Pts) with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5-fluorouracil/leucovorin and PTK787/ZK 222584 or placebo (CONFIRM-1). ASCO Annual Meeting Proceedings.J. Clin. Oncol.23, 16 S (June 1 Supplement): LBA3.
Holbrook, J.J., Liljas, A., Steindel, S.J., and Rossman, M.G. 1975. Lactate dehydrogenase. pp. 191–292 in P. D. Boyer (Ed.),The Enzymes, Academic, New York.
Hong, E.J., Park, S.H., Choi, K.C., Leung, P.C., and Jeung, E.B. 2006. Identification of estrogen-regulated genes by microarray analysis of the uterus of immature rats exposed to endocrine disrupting chemicals.Reprod. Biol. Endocrinol.4:49.
Huang, L.E., Arany, Z., Livingston, D.M., and Bunn, H.F. 1996. Activation of Hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its a subunit.J. Biol. Chem. 271:32253–32259.
Jensen, J.A., Hunt, T.K., Scheuenstuhl, H., and Banda, M.J. 1986. Effect of lactate, pyruvate, and pH on secretion of angiogenesis and mitogenesis factors by macrophages.Lab. Invest.54:574–578.
Jungmann, R.A., and Kiryukhina, O. 2005. Cyclic AMP and AKAP-mediated targeting of protein kinase A regulates lactate dehydrogenase subunit A mRNA stability.J. Biol. Chem. 280:25170–25177.
Kemeny, N., Niedzwiecki, D., Shurgot, B., and Oderman, P. 1989a. Prognostic variables in patients with hepatic metastases from colorectal cancer. Importance of medical assessment of liver involvement.Cancer 63:742–747.
Kemeny, N., Niedzwiecki, D., Reichman, B., Botet, J., Vinciguerra, V., Michaelson, R., Rosenbluth, R., and Deonarine, S. 1989b. Cisplatin and 5-fluorouracil infusion for metastatic colorectal carcinoma. Differences in survival in two patient groups with similar response rates.Cancer 63:1065–1069.
Koukourakis, M.I., Giatromanolaki, A., and Sivridis, E. 2003a. Lactate dehydrogenase isoen-zymes 1 and 5: differential expression by neo-plastic and stromal cells in non-small cell lung cancer and other epithelial malignant tumors.Tumour Biol.24:199–202.
Koukourakis, M.I., Giatromanolaki, A., Sivridis, E., Gatter, K.C., and Harris, A.L. 2006a. Tumour Angiogenesis Research Group. Lactate dehy-drogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway—a report of the Tumour Angiogenesis Research Group.J. Clin. Oncol.24:4301–4308.
Koukourakis, M.I., Giatromanolaki, A., Harris, A.L., and Sivridis, E. 2006b. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma.Cancer Res.66:632–637.
Koukourakis, M.I., Giatromanolaki, A., Sivridis, E., Simopoulos, K., Pastorek, J., Wykoff, C.C., Gatter, K.C., and Harris, A.L. 2001. Hypoxia-regulated carbonic anhydrase-9 (CA9) relates to poor vascu-larization and resistance of squamous cell head and neck cancer to chemoradiotherapy.Clin. Cancer Res. 7:3399–3403.
Koukourakis, M.I., Giatromanolaki, A., Sivridis, E., Simopoulos, C., Turley, H., Talks, K., Gatter, K.C., and Harris, A.L. 2002. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer.Int. J. Radiat. Oncol. Biol. Phys. 53:1192–1202.
Koukourakis, M.I., Giatromanolaki, A., Simopoulos, C., Polychronidis, A., and Sivridis, E. 2005. Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer.Clin. Exp. Metastasis 22:25–30.
Koukourakis, M.I., Giatromanolaki, A., Sivridis, E., Bougioukas, G., Didilis, V., Gatter, K.C., and Harris, A.L. 2003b. Tumour and Angiogenesis Research Group. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, ang-iogenic factor production and poor prognosis.Br. J. Cancer 89:877–885.
Koukourakis, M.I., Giatromanolaki, A., Sivridis, E., Gatter, K.C., Harris, A.L., Trarbach, T., Folprecht, G., and Meinhardt, G. 2007. Intratumoral lactate dehydrogenase 5 (LDH5) protein is associated with the expression of angiogenesis markers and hypoxia in patients with colorectal cancer.J. Clin. Ocol.(suppl)25, 18 S, Part I, Abstr. 4107.
Kuo, L.J., Leu, S.Y., Liu, M.C., Jian, J.J., Hongiun, Cheng, S., and Chen, C.M. 2003. How aggressive should we be in patients with stage IV colorectal cancer?Dis. Colon Rectum 46:1646–1652.
Laughner, E., Taghavi, P., Chiles, K., Mahon, P.C., and Semenza, G.L. 2001. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression.Mol. Cell Biol.21:3995–4004.
Lawson, M.J., White, L.M., Coyle, P., Butler, R.N., Roberts-Thomson, I.C., and Conyers, R.A. 1989. An assessment of proliferative and enzyme activity in transitional mucosa adjacent to colonic cancer.Cancer 64:1061–1066.
Lin, J.T., Wang, W.S., Yen, C.C., Liu, J.H., Yang, M.H., Chao, T.C., Chen, P.M., and Chiou, T.J. 2005. Outcome of colorectal carcinoma in patients under 40 years of age.J. Gastroenterol. Hepatol.20:900–905.
Martinez-Zaguilan, R., Seftor, E.A., Seftor, R.E., Chu, Y.W., Gillies, R.J., and Hendrix, M.J. 1996. Acidic pH enhances the invasive behavior of human melanoma cells.Clin. Exp. Metast.14:176–186.
Mate, J., Duran, R., Lara, S., Pajares, J.M., and Moreno-Otero, R. 1993. A study of the lactic dehydrogenase isoenzyme patterns in the adenoma—carcinoma sequence of the colon.Hepatogastroenterology.40:471–474.
Mottet, D., Dumont, V., Deccache, Y., Demazy, C., Ninane, N., Raes, M., and Michiels, C. 2003. Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells.J. Biol. Chem. 278:31277–31285.
Murray, B., and Wilson, D.J. 2001. A study of metabolites as intermediate effectors in angio-genesis.Angiogenesis 4:71–77
Nemoto, S., Takeda, K., Yu, Z.X., Ferrans, V.J., and Finkel, T. 2000. Role for mitochondrial oxi-dants as regulators of cellular metabolism.Mol. Cell Biol.20:7311–7318.
Pan, L.X., Xu, J.N., and Isaacson, P.G. 1991. Cellular H- and M-type lactate dehydrogenase (LDH) isoenzymes and tumour diagnosis — an immuno-histochemical assessment.J. Pathol.163:53–60.
Pore, N., Gupta, A.K., Cerniglia, G.J., Jiang, Z., Bernhard, E.J., Evans, S.M., Koch, C.J., Hahn, S.M., and Maity, A. 2006. Nelfinavir down-regulates hypoxia-inducible factor 1 and VEGF expression and increases tumor oxygenation: Implications for radiotherapy.Cancer Res.66:9252–9259.
Reddy, R.C., Chen, G.H., Newstaed, M.W., Moore, T., Zeng, T., Tateda, K., and Standiford, T.J. 2001. Alveolar macrophage deactivation in murine septic peritonitis: Role of interleukin-10.Infect. Immun.69:1394–1401.
Rofstad, E.K. 2000. Microenvironment-induced cancer metastasis.Int. J. Radiat. Biol.76:589–605
Rozhin, J., Sameni, M., Ziegler, G., and Sloane, B.F. 1994. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells.Cancer Res.54:6517–6525.
Shim, H., Dolde, C., Lewis, B.C., Wu, C.S., Dang, G., Jungmann, R.A., Dalla-Favera, R., and Dang, C.V. 1997. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.Proc. Natl. Acad. Sci. USA. 94:6658–6663.
Sivridis, E., Giatromanolaki, A., and Koukourakis, M.I. 2005. Proliferating fibroblasts at the invading tumour edge of colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity and oxidative stress.J. Clin. Pathol 58: 1033–1038.
Semenza, G.L., Jiang, B.H., Leung, S.W., Passantino, R., Concordet, J.P., Maire, P., and Giallongo, A. 1996. Hypoxia response elements in the aldo-lase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1.J. Biol. Chem..271:32529–32537.
Stubbs, M., McSheehy, P.M., Griffiths, J.R., and Bashford, C.L. 2000. Causes and consequences of tumour acidity and implications for treatment.Mol. Med. Today 6:15–19.
Vaupel, P., Kallinowski, F., and Okunieff, P. 1989. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review.Cancer Res.49:6449–6465.
Vaupel, P., Kelleher, D.K., and Hockel, M. 2001. Oxygen status of malignant tumors: Pathogenesis of hypoxia and significance for tumor therapy.Semin. Oncol.28:S29–35.
Watine, J., and Friedberg, B. 2004. Laboratory variables and stratification of metastatic colorectal cancer patients: recommendations for therapeutic trials and for clinical practice guidelines.Clin Chim Acta.345:1–15.
Warburg, O. 1931.The Metabolism of Tumors. R. R. Smith, New York
Wykoff, C.C., Beasley, N.J., Watson, P.H., Campo, L., Chia, S.K., English, R., Pastorek, J., Sly, W.S., Ratcliffe, P., and Harris, A.L. 2001. Expression of the hypoxiainducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast.Am. J. Pathol.158:1011–1019
Yuste, A.L., Aparicio, J., Segura, A., Lopez-Tendero, P., Girones, R., Perez-Fidalgo, J.A., Diaz, R., and Calderero, V. 2003. Analysis of clinical prognostic factors for survival and time to progression in patients with metastatic colorectal cancer treated with 5-fluorouracil-based chemotherapy.Clin. Colorectal Cancer 2:231–234.
Yu, Y., Deck, J.A., Hunsaker, L.A., Deck, L.M., Royer, R.E., Goldberg, E., and Vander,Jagt, D.L. 2001. Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4.Biochem. Pharmacol.62:81–89.
Zabel, D.D., Feng, J.J., Scheuenstuhl, H., Hunt, T.K., and Hussain, M.Z. 1996. Lactate stimulation of macrophage-derived angiogenic activity is associated with inhibition of Poly(ADP-ribose) synthesis.Lab. Invest.74:644–649.
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Koukourakis, M.I., Giatromanolaki, A., Sivridis, E. (2009). Colorectal Cancer: Lactate Dehydrogenase (LDH) Activity as a Prognostic Marker. In: Hayat, M.A. (eds) Colorectal Cancer. Methods of Cancer Diagnosis, Therapy, and Prognosis, vol 4. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-9545-0_15
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