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Non-glucose metabolism in cancer cells—is it all in the fat?

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Abstract

Cancer biologists seem to have overlooked tumor metabolism in their research endeavors over the last 80 years of the last century, only to have “rediscovered Warburg” (Warburg et al. 1930; Warburg, Science 123(3191):309–314, 1956) within the first decade of the twenty-first century, as well as to suggest the importance of other, non-glucose-dependent, metabolic pathways such as such as fatty acid de novo synthesis and catabolism (β-oxidation) (Mashima et al., Br J Cancer 100:1369–1372, 2009) and glutamine catabolism (glutaminolysis) (DeBerardinis et al., Proc Nat Acad Sci 104(49):19345–19350, 2007). These non-glucose metabolic pathways seem to be just as important as the Warburg effect, if not potentially more so in human cancer. The purpose of this review is to highlight the importance of fatty acid metabolism in cancer cells and, where necessary, identify gaps in current knowledge and postulate hypothesis based upon findings in the cellular physiology of metabolic diseases and normal cells.

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References

  1. Hannhan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674.

    Article  Google Scholar 

  2. Warburg, O., Wind, F., & Neglers, E. (1930). In O. Warburg (Ed.), Metabolism of tumours (pp. 254–270). London: Constable & Co.

    Google Scholar 

  3. Warburg, O. (1956). On the origin of cancer cells. Science, 123(3191), 309–314.

    Article  PubMed  CAS  Google Scholar 

  4. Koukourakis, M. I., Pitiakoudis, M., Giatromanolaki, A. S., et al. (2006). Oxygen and glucose consumption in gastrointestinal adenocarcinomas: correlation with markers of hypoxia, acidity and aerobic glycolysis. Cancer Science, 97(10), 1056–1060.

    Article  PubMed  CAS  Google Scholar 

  5. Koukourakis, M. I., Giatromanolaki, A., Harris, A. L., & Sivridis, E. (2006). Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Research, 66, 63.

    Article  Google Scholar 

  6. Gottlieb, E., & Tomlinson, I. P. M. (2005). Mitochondrial tumour suppressors: a genetic and biochemical update. Nature Reviews. Cancer, 5, 857–866.

    Article  PubMed  CAS  Google Scholar 

  7. Pike, L. S., Smift, A. L., Croteau, N. J., Ferrick, D. A., & Wu, M. (2010). Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochimica et Biophysica Acta, 1807(6), 726–734.

    Article  Google Scholar 

  8. Gao, P., Tchernyshyov, I., Chang, T. C., Lee, Y. S., Kita, K., Ochi, T., et al. (2009). C-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature, 458(7239), 762–765.

    Article  PubMed  CAS  Google Scholar 

  9. Gurel, B., et al. (2008). Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Modern Pathology, 21, 1156–1167.

    Article  PubMed  CAS  Google Scholar 

  10. Mashima, T., Seimiya, H., & Tsuruo, T. (2009). De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. British Journal of Cancer, 100, 1369–1372.

    Article  PubMed  CAS  Google Scholar 

  11. Koonen, D. P., Glatz, J. F., Bonen, A., & Luiken, J. J. (2005). Long-chain fatty acid and FAT/CD36 translocation in heart and skeletal muscle. Biochimica et Biophysica Acta, 1736(3), 163–180.

    Article  PubMed  CAS  Google Scholar 

  12. Hatzivassiliou, G., Zhao, F., Bauer, D. E., Andreadis, C., Shaw, A. N., Dhanak, D., et al. (2005). ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell, 8(4), 311–321.

    Article  PubMed  CAS  Google Scholar 

  13. Paton, C. M., & Ntambi, J. M. (2009). Biochemical and physiological function of stearoyl-CoA desaturase. American Journal of Physiology, Endocrinology and Metabolism, 297, E28–E37.

    Article  CAS  Google Scholar 

  14. Li, J., Ding, S. F., Habib, N. A., Fermor, B. F., Wood, C. B., & Gilmour, R. S. (1994). Partial characterization of a cDNA for human stearoyl-CoA desaturase and changes in its mRNA expression in some normal and malignant tissues. International Journal of Cancer, 57, 348–352.

    Article  CAS  Google Scholar 

  15. Scaglia, N., & Igal, R. A. (2005). Stearoyl-CoA desaturase is involved in the control of proliferation, anchorage-independent growth, and survival in human transformed cells. Journal of Biological Chemistry, 280, 25339–25349.

    Article  PubMed  CAS  Google Scholar 

  16. Hue, L., & Taegtmeyer, H. (2009). The Randle cycle revisited: a new head for an old hat. American Journal of Physiology, Endocrinology and Metabolism, 297, E578–E591.

    Article  CAS  Google Scholar 

  17. Koltun, D. O., Parkhill, E. Q., Vasilevich, N. I., Glushkov, A. I., Zilbershtein, T. M., et al. (2009). Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors. Bioorganic & Medicinal Chemistry Letters, 19, 2048–2052.

    Article  CAS  Google Scholar 

  18. Scaglia, N., Chisholm, J. W., & Igal, R. A. (2009). Inhibition of stearoylCoA desaturase-1 inactivates acetyl-CoA carboxylase and impairs proliferation in cancer cells: role of AMPK. PLoS One, 4(8), e6812.

    Article  PubMed  Google Scholar 

  19. Nomura, D. K., Long, J. Z., Niessen, S., Hoover, H. S., Ng, S. W., & Cravatt, B. F. (2010). Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell, 140(1), 49–61.

    Article  PubMed  CAS  Google Scholar 

  20. Krycer, J. R., Sharpe, L. J., Luu, W., & Brown, A. J. (2010). The Akt-SREBP nexus: cell signalling meets lipid metabolism. Trends in Endocrinology and Metabolism, 21(5), 268–276.

    Article  PubMed  CAS  Google Scholar 

  21. Van de Sande, T., De Schrijver, E., Heyns, W., Verhoeven, G., & Swinnen, J. V. (2002). Role of phosphatidylinositol 3′-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Research, 62, 642–646.

    PubMed  Google Scholar 

  22. Guo, D., Prins, R. M., Dang, J., Kuga, D., Iwanami, A., Soto, H., et al. (2009). EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Science Signaling, 2(101), ra82.

    Article  PubMed  Google Scholar 

  23. Wullschleger, S., Loewith, R., & Hall, M. N. (2006). TOR signalling in growth and metabolism. Cell, 124(3), 471–484.

    Article  PubMed  CAS  Google Scholar 

  24. Laplante, M., & Sabatini, D. M. (2010). mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. Proceedings of the National Academy of Sciences, 107(8), 3281–3282.

    Article  CAS  Google Scholar 

  25. Luyimbazi, D., Akcakanat, A., McAuliffe, P. F., Zhang, L., Singh, G., Gonzalez-Angulo, A. M., et al. (2010). Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer. Molecular Cancer Therapeutics, 9(10), 2770–2784.

    Article  PubMed  CAS  Google Scholar 

  26. Furuta, E., Pai, S. K., Zhan, R., Bandyopadhyay, S., Watabe, M., Mo, Y. Y., et al. (2008). Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Research, 68(4), 1003–1111.

    Article  PubMed  CAS  Google Scholar 

  27. Vinciguerra, M., Sgroi, A., Veyrat-Durebex, C., Rubbia-Brandt, L., Buhler, L. H., & Foti, M. (2009). Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes. Hepatology, 49(4), 1176–1184.

    Article  PubMed  CAS  Google Scholar 

  28. DeBerardinis, R. J., Lum, J. J., & Thompson, C. B. (2006). Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. Journal of Biological Chemistry, 281, 37372–37380.

    Article  PubMed  CAS  Google Scholar 

  29. D’Erchia, A. M., Tullo, A., Lefkimmiatis, K., Saccone, C., & Sbisa, E. (2006). The fatty acid synthase is a conserved p53 family target from worm to human. Cell Cycle, 5, 750–758.

    Article  PubMed  Google Scholar 

  30. Martel, P. M., Binqham, C. M., Mcgraw, C. J., Baker, C. L., Morganelli, P. M., Meng, M. L., et al. (2006). S14 protein in breast cancer cells: direct evidence of regulation by SREBP-1c, superinduction with progestin, and effects on cell growth. Experimental Cell Research, 312, 278–288.

    PubMed  CAS  Google Scholar 

  31. Graner, E., Tang, D., Rossi, S., Baron, A., Migita, T., Weinstein, L. J., et al. (2004). The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell, 5, 253–261.

    Article  PubMed  CAS  Google Scholar 

  32. Shah, U. S., Dhir, R., Gollin, S. M., Chandran, U. R., Lewis, D., Acquafondata, M., et al. (2006). Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma. Human Pathology, 37, 401–409.

    Article  PubMed  CAS  Google Scholar 

  33. Horton, J. D. (2002). Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochemical Society Transactions, 30(Pt 6), 1091–1095.

    PubMed  CAS  Google Scholar 

  34. Menendez, J. A., Decker, J. P., & Lupu, R. (2005). In support of fatty acid synthase (FAS) as a metabolic oncogene: extracellular acidosis acts in an epigenetic fashion activating FAS gene expression in cancer cells. Journal of Cellular Biochemistry, 94, 1–4.

    Article  PubMed  CAS  Google Scholar 

  35. Pike, L. S., Smift, A. L., Croteau, N. J., Ferrick, D. A., & Wu, M. (2010). Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochimica et Biophysica Acta, 1807(6), 726–734.

    Article  Google Scholar 

  36. Rytkonen, K. T., Williams, T. A., Renshaw, G. M., Primmer, C. R., & Mikinmaa, M. (2011). Molecular evolution of the metazoan PHD-HIF oxygen-sensing system. Molecular Biology and Evolution, 28, 1913–1926.

    Article  PubMed  Google Scholar 

  37. Dang, L., Jin, S., & Su, S. M. (2010). IDH mutations in glioma and acute myeloid leukemia. Trends in Molecular Medicine, 16(9), 387–397.

    Article  PubMed  CAS  Google Scholar 

  38. Ho, P. A., Alonzo, T. A., Kopecky, K. J., Miller, K. L., Kuhn, J., Zeng, R., et al. (2010). Molecular alterations of the IDH1 gene in AML: a Children’s Oncology Group and SouthWest Oncology Group Study. Leukemia, 24, 909–913.

    Article  PubMed  CAS  Google Scholar 

  39. Labussiere, M., Idbaih, A., Wang, X. W., Marie, Y., Boisselier, B., Falet, C., et al. (2010). All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology, 74(23), 1886–1890.

    Article  PubMed  CAS  Google Scholar 

  40. Yen, K. E., Bittinger, M. A., Su, S. M., & Fantin, V. R. (2010). Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene, 29, 6409–6417.

    Article  PubMed  CAS  Google Scholar 

  41. Reitman, Z. J., & Yan, H. (2010). Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. Journal of the National Cancer Institute, 102(13), 932–941.

    Article  PubMed  CAS  Google Scholar 

  42. Biswas, S., Troy, H., Leek, R., Chung, Y. L., Li, J. L., Raval, R. R., et al. (2010). Effects of HIF-1α and HIF2α on growth and metabolism of clear-cell renal cell carcinoma 786-0 xenografts. Journal of Oncology. doi:10.1155/2010/757908.

  43. Rankin, E. B., Rha, J., Selak, M. A., Unger, T. L., Keith, B., Liu, Q., et al. (2009). Hypoxia-inducible factor 2 regulates hepatic lipid metabolism. Molecular and Cellular Biology, 29(16), 4527–4538.

    Article  PubMed  CAS  Google Scholar 

  44. Yao, M., Huang, Y., Shioi, K., Hattori, K., Murakami, T., Nakaigawa, N., et al. (2007). Expression of adipose differentiation-related protein: a predictor of cancer-specific survival in clear cell renal carcinoma. Clinical Cancer Research, 13(1), 152–160.

    Article  PubMed  CAS  Google Scholar 

  45. Zeng, L., Wu, G. Z., Goh, K. J., Lee, Y. M., Ng, C. C., You, A. B., et al. (2008). Saturated fatty acids modulate cell response to DNA damage: implication for their role in tumorigenesis. PLoS One, 3(6), e2329.

    Article  PubMed  Google Scholar 

  46. Liu, H., Liu, Y., & Zhang, J. T. (2008). A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction. Molecular Cancer Therapeutics, 7, 263–270.

    Article  PubMed  Google Scholar 

  47. Menendez, J. A., Vellon, L., Mehmi, I., Oza, B. P., Ropero, S., Colomer, R., et al. (2004). Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 101, 10715–10720.

    Article  PubMed  CAS  Google Scholar 

  48. Anilkumar, N., Uekita, T., Couchman, J. R., Nagase, H., Seiki, M., & Itoh, Y. (2005). Palmitoylation at Cys574 is essential for MT1-MMP to promote cell migration. FASEB, 19, 1326–1328.

    CAS  Google Scholar 

  49. Reddy, J. K., & Hashimoto, T. (2001). Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annual Review of Nutrition, 21, 193–230.

    Article  PubMed  CAS  Google Scholar 

  50. Eaton, S., Bartlett, K., & Pourfarzam, M. (1996). Mammalian mitochondrial beta-oxidation. Biochemistry Journal, 320, 345–357.

    CAS  Google Scholar 

  51. Watkins, P. A., Maiguel, D., Zhenzhen, J., & Pevsner, J. (2007). Evidence for 26 distinct acyl-CoA synthetase genes in the human genome. Journal of Lipid Research, 48, 2736–2750.

    Article  PubMed  CAS  Google Scholar 

  52. Pei, Z., Sun, P., Huang, P., Lal, B., Laterra, J., & Watkins, P. A. (2009). Acyl-CoA synthetase VL3 knockdown inhibits human glioma cell proliferation and tumorigenicity. Cancer Research, 69(24), 9175–9182.

    Article  PubMed  CAS  Google Scholar 

  53. Yamoutpour, F., Bodempudi, V., Park, S. E., Pan, W., Mauzy, M. J., Kratzke, R. A., et al. (2008). Gene silencing for epidermal growth factor receptor variant III induces cell-specific cytotoxicity. Molecular Cancer Therapeutics, 7(11), 3586–3597.

    Article  PubMed  CAS  Google Scholar 

  54. Bartlett, K., & Eaton, S. (2004). Mitochondrial β-oxidation. European Journal of Biochemistry, 271, 462–469.

    Article  PubMed  CAS  Google Scholar 

  55. Zhang, J., Zhang, W., Zou, D., Chen, G., Wan, T., & Zhang, M. (2002). Cloning and functional characterization of ACAD-9, a novel member of human acyl-CoA dehydrogenase family. Biochemical and Biophysical Research Communications, 297, 1033–1042.

    Article  PubMed  CAS  Google Scholar 

  56. Rinaldo, P., Matern, D., & Bennett, M. J. (2002). Fatty acid oxidation disorders. Annual Review of Physiology, 64, 477–502.

    Article  PubMed  CAS  Google Scholar 

  57. Orii, K. E., Aoyama, T., Wakui, K., Kukushima, Y., Miyajima, Y. S., et al. (1997). Genomic and mutational analysis of the mitochondrial trifunctional protein β-subunit (HADHB) gene in patients with trifunctional protein deficiency. Human Molecular Genetics, 6(8), 1215–1224.

    Article  PubMed  CAS  Google Scholar 

  58. Orii, K. E., Orii, K. O., Souri, M., Orii, T., Kondo, N., Hashimoto, T., et al. (1999). Genes for the human mitochondrial trifunctional protein alpha- and beta-subunits are divergently transcribed from a common promoter region. Journal of Biological Chemistry, 274(12), 8077–8084.

    Article  PubMed  CAS  Google Scholar 

  59. www.sanger.ac.uk/genetics/CGP/cosmic. Accessed 31 March 2012.

  60. Yang, Y., Sharma, R., Sharma, A., Awasthi, S., & Awasthi, Y. C. (2003). Lipid peroxidation and cell cycle signalling: 4-hydroxynoneal, a key molecule in stress mediated signalling. Act Biochimica Polonica, 50(2), 319–336.

    CAS  Google Scholar 

  61. Russell, A. P., Somm, E., Praz, M., Crettenand, A., Hartley, O., Melotti, A., et al. (2003). UCP3 protein regulation in human skeletal muscle fibre types I, Ia and IIx is dependent on exercise intensity. The Journal of Physiology, 550(3), 855–861.

    Article  PubMed  CAS  Google Scholar 

  62. Samudio, I., Fiegl, M., & Andreeff, M. (2009). Mitochondrial uncoupling and the Warburg effect: molecular basis for the reprogramming of cancer cell metabolism. Cancer Research, 69(6), 2163–2166.

    Article  PubMed  CAS  Google Scholar 

  63. Samudio, I., Fiegl, M., McQueen, T., Clise-Dwyer, K., & Andreeff, M. (2008). The Warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. Cancer Research, 68, 5198–5205.

    Article  PubMed  CAS  Google Scholar 

  64. Derdak, Z., Mark, N. M., Beldi, G., et al. (2008). The mitochondria uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Research, 68, 2813–2819.

    Article  PubMed  CAS  Google Scholar 

  65. Echtay, K. S., Roussel, D., St-Pierre, J., Jekabsons, M. B., Cadenas, S., Stuart, J. A., et al. (2002). Superoxide activates mitochondrial uncoupling proteins. Nature, 415, 96–99.

    Article  PubMed  CAS  Google Scholar 

  66. Passos, J. F., Saretzki, G., Ahmed, S., Nelson, G., Richter, T., Peters, H., et al. (2007). Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biology, 5(5), e110.

    Article  PubMed  Google Scholar 

  67. Giordano, A., Calvani, M., Petillo, O., Grippo, P., Tuccillo, F., Melone, M. A., et al. (2005). tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine plamitoyltransferase-1. Cell Death and Differentiation, 12(6), 603–613.

    Article  PubMed  CAS  Google Scholar 

  68. Paumen, M. B., Ishida, Y., Han, H., Muramatsu, M., Eguchi, Y., Tsujimoto, Y., et al. (1997). Direct interaction of the mitochondrial membrane protein carnitine palmitoyltransferase I with BCL-2. Biochemical and Biophysical Research Communications, 231(3), 523–525.

    Article  PubMed  CAS  Google Scholar 

  69. Elzein, E., Ibrahim, P., Koltun, D. O., Rehder, K., Shenk, K. D., Marquart, T. A., et al. (2004). CVT-4325: a potent fatty acid oxidation inhibitor with favourable oral bioavailability. Bioorganic & Medicinal Chemistry Letters, 14(24), 6017–6021.

    Article  CAS  Google Scholar 

  70. Zhang, C. Y., Parton, L. E., Ye, C. P., Krauss, S., Shen, R., Lin, C. T., et al. (2006). Genepin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high-glucose induced β cell dysfunction in isolated pancreatic islets. Cell Metabolism, 3(6), 417–427.

    Article  PubMed  CAS  Google Scholar 

  71. Cao, W., Liu, N., Tang, S., Bao, L., Shen, L., Yuan, H., et al. (2008). Acetyl-coenzyme A acyltransferase 2 attenuates the apoptotic effects of BNIP3 in two human cell lines. Biochimica et Biophysica Acta, 1780(6), 873–880.

    Article  PubMed  CAS  Google Scholar 

  72. DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., et al. (2007). Beyond aerobic glycolysis: transformed cells can engage in the glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Nat Acad Sci, 104(49), 19345–19350.

    Article  PubMed  CAS  Google Scholar 

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Biswas, S., Lunec, J. & Bartlett, K. Non-glucose metabolism in cancer cells—is it all in the fat?. Cancer Metastasis Rev 31, 689–698 (2012). https://doi.org/10.1007/s10555-012-9384-6

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