Anaplerosis in cancer: Another step beyond the warburg effect


Biosynthesis is up-regulated in tumors and thus the demand for anabolic intermediates is increased. The metabolic routes providing the building blocks for macromolecules are thus a very attractive target as they are not normally up-regulated in a normal quiescent cell. Some routes for glycolysis-derived intermediates production have been identified, but these do not constitute the whole pool of biosynthetic molecules in the cell, as many of these derive from mitochondria in the Krebs cycle. Indeed, this metabolic pathway is considered a “biosynthetic hub” from which anabolism is fed. If a metabolite efflux is indeed occurring, anaplerotic reactions must keep a steady supply of substrates. In spite of this obvious relevance of anaplerosis, it has been poorly characterized in the malignant cell context. Glutaminolysis and and pyruvate carboxylation are two pathways that function in an anaplerotic fashion. In spite of the increasing evidence implicating these two processes in cancer metabolism their role as intermediate providers is overlooked. In this review we analyze the implications of an active anaplerosis in cancer and we discuss experimental evidence showing the relevance of these metabolic routes in tumor physiology.

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Ochoa-Ruiz, E. and Diaz-Ruiz, R. (2012) Anaplerosis in cancer: Another step beyond the warburg effect. American Journal of Molecular Biology, 2, 291-303. doi: 10.4236/ajmb.2012.24031.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Koppenol, W.H., Bounds P.L. and Dang, C.V. (2011) Otto Warburg’s contribution to current concepts of cancer metabolism. Nature Reviews on Cancer, 11, 325-37. doi:10.1038/nrc3038
[2] Jones, T. and Price, P. (2012) Development and experimental medicine applications of PET in oncology. The Lancet Oncology, e116-25. doi:10.1016/S1470-2045(11)70183-8
[3] Warburg, O. (1956) On the origin of cancer cells. Science, 123, 309-14. doi:10.1126/science.123.3191.309
[4] Eng, C., Kiuru, M., Fernandez, M.J., and Aaltonen, M.A. (2003) A role for mitochondrial enzymes in inherited neoplasia and beyond. Nature Reviews on Cancer, 3, 193-202. doi:10.1038/nrc1013
[5] Pollard, P.J., Brière, J.J., Alam, N.A., Barwell, J., Barclay, E., Wortham, N.C., Hunt, T., Mitchell, M., Olpin, S., Moat, S.J., Hargreaves, I.P., Heales, S.J., Chung, Y.L., Griffiths, J.R., Dalgeish, A., McGrath, J.A., Gleeson, M.J., Hodgson, S.V., Poulsom, R., Rustin, P. and Tomlinson, I.P. (2005) Accumulation of Krebs cycle intermediates and overexpression on HIF1alpha in tumours which result from germline FH and SDH mutations, Human Molecular Genetics, 14, 2231-9. doi:10.1093/hmg/ddi227
[6] Matoba, S., Kang, J.G., Patino, W.D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P.J., Bunz, F. and Hwang, P.M. (2006) p53 regulates mitochondrial respiration. Science, 312, 1650-3. doi:10.1126/science.1126863
[7] Diaz-Ruiz, R., Uribe-Carvajal, S., Devin, A. And Rigoulet, M. (2009) Tumor cell energy metabolism and its common features with yeast metabolism. Biochimica et Biophysica Acta – Reviews on Cancer, 1796, 252-65.
[8] Pastorino, J.G., Shulga, N. and Hoek, J.B. (2002) Mito-chondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. The Journal of Bio-logical Chemistry, 277, 7610-8. doi:10.1074/jbc.M109950200
[9] Yang, W., Xia, Y., Ji, H., Zheng. Y., Liang, J., Hwang, W., Gao, X., Aldape, K. and Luz Z. (2012) Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature, 480, 118-22.
[10] Yang, W., Xia, Y., Hawke, D., Li, X., Liang, J., Xing, D., Aldape, K., Hunter, T., Alfred Yung, W.K. and Lu, Z. (2012) PKM2 phosphorylates histone H2 and promotes gene transcription and tumorigenesis. Cell, 150, 685-96. doi:10.1016/j.cell.2012.07.018
[11] Cairns, R.A., Harris, I.S. and Mak, T.W. (2011) Regulation of cancer cell metabolism. Nature Reviews on Cancer, 11,85-95. doi:10.1038/nrc2981
[12] Semenza, G.L., Roth, P.H., Fang, H.M. and Wang, G.L. (1994) Transcriptional regulations of gene encoding gly-colytic enzymes by hypoxya-inducible factor 1. Journal of Biological Chemistry, 269, 23757-63.
[13] Kim, J.W., Tchernyshyov, I., Semenza, G.L. and Dang, C.V. (2006) HIF-mediated expression of pyruvate dehy-drogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism, 3, 177-85. doi:10.1016/j.cmet.2006.02.002
[14] Lee, K.H., Hsu S.C., Guh, J.H., Yang, H.C., Wang, D., Kulp. S.K., Shapiro, C.L. and Chen C.S. (2011) Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator, The Journal of Biological Chemistry, 286, 39247-58. doi:10.1074/jbc.M111.264598
[15] Sakamaki, T., Casimiro, M.C., Ju, X., Quong, A.A., Katiyar, S., Liu, M., Jiao, X., Li, A., Zhang, X., Lu, Y., Wang, C., Byers, S., Nicholson, R., Link, T., Shemluck, M., Yang, J., Fricke, S.T., Novikoff, P.M., Papanikolaou, A., Arnold, A., Albanese, C. and Pestell, R. (2006) Cyclin D1 determines mitochondrial function in vivo, Molecular and Cellular Biology, 26, 5449-69. doi:10.1128/MCB.02074-05
[16] Landor, S.K., Mutvei, A.P., Mamaeva, V., Jin, S., Busk, M., Borra, R., Gr?nroos, T.J., Kronqvist, P., Lendahl, U. and Sahlgren, C.M. (2011) Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms, Proceedings of the National Academy if Sciences USA, 108, 18814-9.
[17] Jones, R.G. and Thompson, C.B. (2009) Tumor suppressors and cell metabolism: a recipe for cancer growth, Genes & Development, 23, 537-48. doi:10.1101/gad.1756509
[18] Ko, Y.H., Pedersen, P.L. and Geschwind, J.F. (2001) Glucose catabolism in the Rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Letters, 173, 83-91. doi:10.1016/S0304-3835(01)00667-X
[19] Vander Heiden, M.G., Christofk, H.R., Schuman, E., Subtenly, A.O., Sharfi, H., Harlow, E.E., Xian, J., Cantley, L.C. (2010) Identification of small molecule inhibitors of pyruvate kinase M2. Biochemical Pharmacology, 79, 1118-24. doi:10.1016/j.bcp.2009.12.003
[20] Bonnet, S., Archer, S.L., Allalunis-Turner, J., Haromy, A., Beaulieu, C., Thompson, R., Lee, C.T., Lopaschuk, G.D., Puttagunta, L., Bonnet, S., Harry, G., Hashimoto, K., Porter, C.J., Andrade, A., Thebaud, B. and Michelakis, L.D. (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell, 11, 37-51. doi:10.1016/j.ccr.2006.10.020
[21] Semenza, G.L. (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends in Pharmacological Sciences, 33, 207-14. doi:10.1016/
[22] Moreno-Sánchez, R., Rodríguez-Enríquez, S., Marín-Hernández, A.. and Saavedra, E. (2007) Energy metabolism in tumor cells. The FASEB Journal, 274, 1393-418.
[23] Metallo, C., Gameiro, P.A., Bell. E.L., Mattiani, K.R., Yang, J., Hiller, K., Jewell, C.M., Johnson, Z.R., Irvine, D.J., Guarente, L., Kelleher, J.K., Vander Heiden, M.G., Iliopuolos, O, and Stephanopoulos, G. (2012) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature, 481, 380-4.
[24] Lu, C., Ward, P.S., Kapoor, G.S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C.R., Khanin, R., Figueroa, M.G., Melnick, A., Wellen, K.E., O’Rourke, D.M., Berger, S.L., Chan, T.A., Levine, R.L., Mellinghoff, I.K. and Thompson, C.B. (2012) IDH1 mutation impairs demethylation and results in a block to cell differentiation. Nature, 483, 474-8. doi:10.1038/nature10860
[25] Wellen, K.E., Hatzivassiliou, G., Sachdeva, U.M., Bui, T.V., Cross, J.R. and Thompson, C.B. (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science, 324, 1076-80. doi:10.1126/science.1164097
[26] Vander Heiden, M.G., Cantley, L.C. and Thompson, C.B. (2009) Understanding the Warburg effect: the metabolic requirements for cell proliferation. Science, 324, 1029-33. doi:10.1126/science.1160809
[27] Des Rosiers, C., Labarthe, F., Lloyd, S.G. and Chatham, J.C. (2011) Cardiac anaplerosis in health and disease. Cardiovascular research, 90, 210-9. doi:10.1093/cvr/cvr055
[28] Owen, O.E., Kalhan, S.C. and Hanson, R.W. (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. The Journal of Biological Chemistry. 277, 30409-30412. doi:10.1074/jbc.R200006200
[29] Marin-Valencia, I., Roe, C.R. and Pascual, J.M. (2010) Pyruvate carboxylase deficiency: mechanism, mimics and anaplerosis. Molecular Genetics and Metabolism, 101, 9-17. doi:10.1016/j.ymgme.2010.05.004
[30] Jitrapakdee, S., St. Maurice, M., Rayment, I., Cleland, W.W., Wallace, J.C. and Attwood, P.V. (2008). Structure, Mechanism and Regulation of Pyruvate Carboxylase. Biochemistry Journal. 413, 369- 387. doi:10.1042/BJ20080709
[31] Hohmeier, H.E., Mulder, H., Chen, G., Henkel-Rieger, R., Prentki, M. and Newgard, C.B. (2000) Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and –independent glucose-stimulated insulin secretion. Diabetes, 49, 424-430. doi:10.2337/diabetes.49.3.424
[32] Jitrapakdee, S., Vidal-Puig, A. and Wallace, J.C. ( 2006) Anaplerotic roles of pyruvate carboxylase in mammalian tissues. Cellular and Molecular Life Sciences, 63, 843-854. doi:10.1007/s00018-005-5410-y
[33] Merritt, M.E., Harrison, C., Sherry, A.D., Malloy, C.R. and Burgess, S.C. (2011). Flux through hepatic pyruvate carboxylase and phosphoenolpyruvate carboxykinase detected by hyperpolarized 13 C magnetic resonance. Proceedings of the National Academy of Sciences USA. 108, 19084 –19089. doi:10.1073/pnas.1111247108
[34] Hertz, L., Peng, L. and Dienel, G.A. (2007) Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. Journal of Cerebral Bloodflow and Metabolism, 27, 219-49. doi:10.1038/sj.jcbfm.9600343
[35] Lapidot, A. and Gopher, A. (1994) Cerebal metabolic compartmentation. Estimation of glucose flux via pyruvate carboxylase/pyruvate dehdrogenase by 13C NMR isotopomer analysis of D-[13C]glucose metabolites. Journal of Biological Chemistry, 269, 198-208.
[36] De la Rosa, V., Campos-Sandoval, J.A., Marín-Rufían, M., Cardona, C., Matés, J.M., Segura, J.A., Alonso, F.J. and Márquez, J. (2009) A novel glutaminase isoform in mammalian tissues. Neurochemistry international, 55, 76-84. doi:10.1016/j.neuint.2009.02.021
[37] Prebil, M., Jensen, J., Zorec, R. and Kreft, M. (2011) Astrocytes and energy metabolism, Archives of Physiology and Biochemistry, 117, 64-9. doi:10.3109/13813455.2010.539616
[38] Guppy, M., Leedman, P., Zu, X. and Russel, V. (2002) Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. The Biochemical Journal. 364, 309-15.
[39] Whitaker-Menezes, D., Martinez-Outchoorn, U.E., Flomenberg, N., Birbe, R.C., Witkiweicz, A.K., Howell, A., Pavlides, S., Tsirigos, A., Ertel, A., Pestell, R.G., Broda, P., Minetti, C., Lisanti, M.P. and Sotgia, F. (2011) Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle. 10, 4047-64. doi:10.4161/cc.10.23.18151
[40] Rodríguez-Enríquez, S., Vital-González, P.A., Flores-Rodríguez, F.L., Marín-Hernández, A., Ruiz-Azuara, L. and Moreno-Sánchez, R. (2006) Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells. Toxicology and Applied Pharmacology, 215, 208-17. doi:10.1016/j.taap.2006.02.005
[41] Martin, M., Beauvoit, M., Voisin, P.J., Canioni, P., Guérin, B. and Rigoulet, M. (1998) Energetic and morphological plasticity of C6 glioma cells grown on 3-D support; effect of transient glutamine deprivation. Journal of Bioenergetics and Biomembranes, 30, 565-778. doi:10.1023/A:1020584517588
[42] Marin-Valencia, I., Yang, C., Mashimo, T., Cho, S., Baek, H., Yang, X.L., Rajagopalan, K.N., Maddie, M., Vemireddy, V., Zhao, Z., Cai, L., Good, L., Tu, B.P., Hatanpaa, K.J., Mickey, B.E., Matés. J.M., Pascual, J.M., Maher, E.A., Malloy, C.R., DeBerardinis, R.J. and Bachoo, R.M. (2012) Analysis of tumor metabolism reveals glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metabolism, 15, 827-37. doi:10.1016/j.cmet.2012.05.001
[43] Das, S.K., Eder, S., Schauer, S., Diwoky, C., Temmel, H., Guertl, B., Gorkiewicz, G., Tamilarasan, K.P., Kumari, P., Trauner, M., ZimmermannR., Vesely, P., Haemmerle, G., Zechner, R. and Hoefler, G. (2011) Adipose triglyceride lipase contributes to cancer-associated cachexia. Science, 333, 233-8. doi:10.1126/science.1198973
[44] Nieman, K.M., Kenny, H.A., Penicka, C.V., Ladanyi, A., Buell-Gutbrod, R., Zillhardt, M.R., Romero, I.L., Carey, M.S., Mills, G.B., Hotamisligil, G.S., Yamada, S.D., Peter, M.E., Gwin, K. and Lengyel, E. (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Medicine, 17, 1498-503. doi:10.1038/nm.2492
[45] Rodríguez-Enríquez, S., Juárez, O., Rodríguez-Zavala, J.S. and Moreno-Sánchez, R. (2001) Multisite control of the Crabtree effect in ascites hepatoma cells. European Journal of Biochemistry, 268, 2512-9. doi:10.1046/j.1432-1327.2001.02140.x
[46] Rossignol, R., Gillkerson, R., Aggeler, R., Yamagata, K., Remington, S.J. and Capaldi, R.A. (2004) Energy substrate modulates mitochondria structure and oxidative capacity in cancer cells. Cancer Research, 64, 985-93. doi:10.1158/0008-5472.CAN-03-1101
[47] Schroeder, T., Yuan, H., Viglianti, B.L., Peltz, C., Asopa, S., Vujaskovic, Z. and Dewhirst, M.W. (2005) Spatial heterogeneity and oxygen dependence of glucose consumption in R3230Ac and fibrosarcomas of the Fischer 344 rat. Cancer Research, 65, 5163-71. doi:10.1158/0008-5472.CAN-04-3900
[48] Sonveaux, P., Végran, F., Schroeder, T., Wergin, M.C., Verrax, J., Rabbani, Z.N., De Seadleer, C.J., Kennedy, K.M., Diepart, C., Jordan, B.F., Kelley, M.J., Gallez, B., Wahl, M.L., Feron, O. and Dewhirst, W. (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. The Journal of Clinical Investigation, 118, 3930-42.
[49] Martinez-Outschoorn, U.E., Pestell, R.G., Howell, A., Tykocinski, M.L., Nagajyothi, F., Machado, F.S., Tanowitz, H.B., Sotgia, F. and Lisanti, M.P. (2011) Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles’ heel of tumor cells. Cell Cycle, 10, 4208-16. doi:10.4161/cc.10.24.18487
[50] Pfeiffer, T., Schuster, S. and Bonhoeffer, S. (2001) Co-operation and competition in the evolution of ATP-producing pathways. Science, 292, 504-7. doi:10.1126/science.1058079
[51] Vander Heiden, M.G., Locasale, J.W., Swanson, K.D., Sharfi, H., Heffron G.J., Amador-Noguez, D., Christofk, H.R., Wagner, G., Rabinowitz, J.D., Asara, J.M. and Cantley, L.C. (2010) Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science, 329, 1492-9. doi:10.1126/science.1188015
[52] Locasale, J.W., Grassian, A.R., Melman, T., Lyssiotis, C.A., Mattaini, K.R., Bass, A-J., Heffron, G., Metallo, C.M., Muranen, T., Sharfi, H., Sasaki, A.T., Anastasiou, D., Mullarky, E., Vokes, N.I., Sasaki, M., Beroukhim, R., Stephanopoulos, G., Ligon, A.H., Meyerson, M., Richardosn, A.L., Chin, L., Wagner, G., Asara, J.M., Brugge, J.S., Cantley, L.C., Vander Heiden, M.G. (2011) Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genetics, 43, 869-74. doi:10.1038/ng
[53] Hitosugi, T., Kang, S., Vander Heiden, M.G., Chung, T.W., Elf, S., Lythgoe, K., Dong, S., Lonial, S., Wang, X., Chen, G.Z., Xie, J., Gu, T.L., Polakiewicz, R.D., Roesel, J.L., Boggon, T.J., Khuri, F.R., Gilliland, D.G., Cantley, L.C., Kaufman, J. and Chen J. (2009) Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Science Signaling, 2, ra73. doi:10.1126/scisignal.2000431
[54] Frezza, C., Zheng, L., Folger, O., Rajagopalan, K.N., McKenzie, E.D., Jerby, L., MIcaroni, M., Chaneton, B., Adam, J., Hedley, A., Kalna, G., Tomlinson, I.P., Pollard, P.J., Watson, D.G., DeBerardinis, R.J., Shlomi, T., Ruppin, E. and Gottlieb, E. (2011) Haem oxygenase is synthetically lethal with the tumor suppressor fumarate hydratase. Nature, 477, 225-8. doi:10.1038/nature10363
[55] Pelicano, H., Martin, D.S., Xu, R.H. and Huang, P. (2006) Glycolysis inhibition for anticancer treatment. Oncogene, 25, 463-4646. doi:10.1038/sj.onc.1209597
[56] Sauer, L.A., Stayman, J.W. 3rd and Dauchy, R.T. (1982) Amino acid, glucose and lactic acid accumulation in vivo by rat tumors. Cancer Research, 42, 4090-7.
[57] DeBerardinis, R.J. and Cheng, T. (2010) Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene, 29, 313-324. doi:10.1038/onc.2009.358
[58] Pérez-Gómez, C., Campos-Sandoval, J.A., Alonso, F.J., Segura, J.A., Manzanares, E., Ruiz-Sánchez, P., González, M.E., Márquez, J., Matés, J.M. (2005) Co-expression of glutaminase K and L isoenzymes in human tumour cells. The Biochemical Journal, 386, 535-42. doi:10.1042/BJ20040996
[59] Cassago, A., Ferreira, A.P., Ferreira, I.M., Fornezari, C., Gomes, E.R., Greene, K.S., Pereira, H.M., Garratt, R.C., Dias, S.M. and Ambrosio, C.L. (2012) Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism, Proceedings of the National Academy of Sciences of the United States of America, 109, 1092-7. doi:10.1073/pnas.1112495109
[60] Gómez-Fabre, P.M., Aledo, J.C., Del Castillo-Olivares, A., Alonso, F.J., Nu?ez de Castro, I., Campos, J.A. and Márquez, J. (2000) Molecular cloning, sequencing and expression studies of the human breast cancer glutaminase. The Biochemical Journal, 345, 365-75. doi:10.1042/0264-6021:3450365
[61] Szeliga, M., Sidoryk, M., Matyja, E., Kowalczyk, P. and Albrecht, J. (2005) Lack of expression of the liver-type glutaminase (LGA) mRNA in human malignant gliomas. Neuroscience Letters, 374, 171-3. doi:10.1016/j.neulet.2004.10.051
[62] Matsuno, I. and Hirai, H. (1989) Glutamine synthetase and glutaminase activities in various hepatoma cells. Biochemistry International, 19, 219-25.
[63] Colombo, S.L., Palacios-Callender, M., Frakich, N., De Leon, J., Schmitt, C.A., Boorn, L., Davis, N., Moncada, S. (2010) Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes, Proceedings of the National Academy of Sciences of the United States of America, 107, 18868-73. doi:10.1073/pnas.1012362107
[64] Colombo, S.L., Palacios-Callender, M., Frackich, N., Carcamo, S., Kovacs, I., Tudzarova, S. and Moncada, S. (2011) Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells. Proceedings of the National Academy of Sciences of the United States of America, 108, 21069-74. doi:10.1073/pnas.1117500108
[65] Garedew, A., Andreassi, C. and Moncada, S. (2012) Mitochondrial dynamics, biogenesis, and function are coordinated with the cell cycle by APC/C CDH1. Cell Metabolism, 15, 466-79. doi:10.1016/j.cmet.2012.03.003
[66] Wise, D.R., DeBerardinis, R.J., Mancuso, A., Sayed, N., Zhang, X.Y., Pfeiffer, H.K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S.B. and Thompson, C.B. (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proceedings of the National Academy of Sciences of the United States of America, 105, 18782-7. doi:10.1073/pnas.0810199105
[67] Li, F., Wang, Y., Zeller, K.I., Potter, J.J., Wonsey, D.R., O’Donell, K.A., Kim, J.W., Yustein, J.T., Lee, L.A. and Dang, C.V. (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Molecular and Cellular Biology, 25, 6225-34. doi:10.1128/MCB.25.14.6225-6234.2005
[68] DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G. and Thompson, C.B. (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metabolism, 7, 11-30. doi:10.1016/j.cmet.2007.10.002
[69] Le, A., Lane, A.N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C.J., Slusher, B.S., Zhang, H., Zimmerman, L.J., Liebler, D.C., Slebos, R.J., Lorkiewicz, P.K., Higashi, R.M., Fan, T.W. and Dang, C.V. (2012) Glucose-independent glucose metabolism via TCA cycling for proliferation and survival in B cells. Cell Metabolism, 15, 110-21. doi:10.1016/j.cmet.2011.12.009
[70] Parlo, R.A. and Coleman, R.S. (1984) Enhanced rate of citrate export from cholesterolrich hepatoma mitochondria. The truncated Krebs cycle and other metabolic ramifications of mitochondrial membrane cholesterol. The Journal of Biological Chemistry, 259, 9997-10003.
[71] Fillipp, F.V., Scott, D.A., Ronai, Z.A., Osterman, A.L. and Smith, J.W. (2012) Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment Cell & Melanoma Research, 25, 375-383. doi:10.1111/j.1755-148X.2012.00989.x
[72] Seltzer, M.J., Bennett, B.D., Joshi, A.D., Gao, P., Thomas, A.G., Ferraris, D.V., Tsukamoto, T., Rojas, C.J., Slusher, B.S., Rabinowitz, J.D., Dang, C.V. and Riggins, G.J. (2010) Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Research, 70, 8981-7. doi:10.1158/0008-5472.CAN-10-1666
[73] Katt, W.P., Ramachandran, S., Erickson, J.W. and Cerione, R.A. (2012) Dibenzophenanthridines as inhibitors of glutaminase C and cancer cell proliferation. Molecular Cancer Therapeutics, 11, 1269-78. doi:10.1158/1535-7163.MCT-11-0942
[74] Wang, J.B., Erickson, J.W., Fuji, R., Ramachandran, S., Gao, P., Dinavahi, R., Wilson, K.F., Ambrosio, A.L., Dias, S.M., Dang, C.V. and Cerione R.A. (2010) Targeting mitochondrial glutaminase activity oncogenic transformation. Cancer Cell, 18. 207-19. doi:10.1016/j.ccr.2010.08.009
[75] Portais, J.C., Schuster, R., Merle, M. and Canioni, P. (1993) Metabolic flux determination in C6 glioma cells using carbon-13 distribution upon [1-13C]glucose incubation. European Journal of Biochemistry, 217, 47-68. doi:10.1111/j.1432-1033.1993.tb18265.x
[76] Hammond, K.D. and Balinsky, D. (1978) Activities of key gluconeogenic enzymes and glycogen synthase in rat and human livers, hepatomas, and hepatoma cell cultures. Cancer Research, 38, 1317-22.
[77] Sato, T., Kashima, K., Gamachi, A., Daa, T., Nakayama, I. and Yokoyama, S. (2002) Immunohistochemical localization of pyruvate carboxylase and carbamyl-phosphate synthetase I in normal and neoplastic human pancreatic tissues. Pancreas, 25, 130-5. doi:10.1097/00006676-200208000-00003
[78] Bramwell, M. and Humm, S.M. (1992) Variations in the relative amount of biotin-containing enzymes present in both tumorigenic and non-tumorigenic hybrid cells and other cell lines. Biochimica et Biophysyca Acta, 1139, 115-21. doi:10.1016/0925-4439(92)90090-A
[79] Liu, K.J., Kleps, R., Henderson, T. and Nyhus, L. (1991) 13C NMR study of hepatic pyruvate carboxylase activity in tumor rats. Biochemical and Biophysical Research Communications, 179, 366-71. doi:10.1016/0006-291X(91)91379-Q
[80] Díaz-Ruiz, R., Rigoulet, M. and Devin, A. (2011) The Warburg and Crabtree effects: on the origin of cancer cell energy metabolism and of yeast glucose repression. Bio-chimica et Biophysica Acta, 1807, 568-76. doi:10.1016/j.bbabio.2010.08.010
[81] Lee, S.Y., Jeon, H.M., Ju, M.K., Kim, C.H., Yoon, G., Han, S.I., Park, H.G. and Kang, H.S. (2012) Wnt/Snail signaling regulates cytochrome c oxidase and glucose metabolism. Cancer Research, 72, 3607-17. doi:10.1158/0008-5472.CAN-12-0006
[82] Godlewski, J., Nowicki, N.O., Bronisz, A., Nouvo, G., Palatini, J., De Lay, M., Van Brocklyn, J., Ostrowski, M.C., Chiocca, E.A. and Lawler, S.E. (2010) MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells, Molecular Cell, 37, 620-32. doi:10.1016/j.molcel.2010.02.018
[83] Kimura, Y., Kashima, K., Daa, T., Kondo, Y., Yada, K., Sasaki, A., Matsumoto, T., Kitano, S., Kubo, N. and Yokoyama, S. (2005) Biotinrich intranuclear inclusions in morule-lacking adenocarcinoma of the gallbladder: a new category of “neoplastic/non-morular” lesions. Virchows Archiv: an international journal of pathology, 446, 194-9.
[84] Cheng, T., Sudderth, J., Yang, C., Mullen, A.R., Jin, E.S., Matés, J.M. and DeBerardinis, R.J. (2011) Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. . Proceedings of the National Academy of Sciences of the United States of America, 108, 8674-9. doi:10.1073/pnas.1016627108
[85] Fan, T.W., Lane, A.N., Higashi, R.M., Faraq, M.A., Gao, H., Bousamra, M. and Miller, D.M. (2009) Altered regulation of metabolic pathways in human lung cancer discerned by (13)C stable isotope-resolved metabolomics (SIRM). Molecular Cancer, 8, 41. doi:10.1186/1476-4598-8-41
[86] Budczies, J., Denkert, C., Müller, B.M., Brockm?ller, S.F., Klauschen, F., Gy?rffy, B., Dietel, M., Richter-Ehrenstein, C., Marten, U., Salek, R.M., Griffin, J.L., Hilvo, M., Oresic, M., Wohlgemuth, G. and Fiehn, O. (2012) Remodeling of central metabolism in invasive breast cancer in invasive breast cancer compared to normal breast tissue: a GC-TOFMS based metabolomics study. BMC Genomics, 13, 334.

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