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The multifaceted roles of fatty acid synthesis in cancer

Key Points

  • Cancer cells activate de novo fatty acid synthesis to provide essential structural components and substrates for the generation of signalling molecules.

  • Transcriptional regulators of lipid biosynthesis are downstream targets of oncogenes and tumour suppressor pathways.

  • Cancer cells can induce lipid uptake to respond to changes in environmental conditions.

  • Dependence of cancer cells on lipid synthesis or uptake may be defined by the conditions of the tumour microenvironment.

  • Lipid synthesis contributes to cellular processes linked to tumour progression.

  • Multiple lipid metabolism enzymes have been investigated as potential targets for cancer therapy.

Abstract

Lipid metabolism, in particular the synthesis of fatty acids (FAs), is an essential cellular process that converts nutrients into metabolic intermediates for membrane biosynthesis, energy storage and the generation of signalling molecules. This Review explores how different aspects of FA synthesis promote tumorigenesis and tumour progression. FA synthesis has received substantial attention as a potential target for cancer therapy, but strategies to target this process have not yet translated into clinical practice. Furthermore, efforts to target this pathway must consider the influence of the tumour microenvironment.

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Figure 1: Fatty acid synthesis in cancer.
Figure 2: Fatty acid synthesis and uptake.
Figure 3: Regulation of SREBP activity on multiple levels.
Figure 4: Metabolic flexibility in the tumour microenvironment.
Figure 5: Lipids contribute to signalling processes in cancer cells.

References

  1. 1

    Warburg, O., Posener, K. & Negelein, E. Über den Stoffwechsel der Carcinomzelle. Biochem. Zeitschr. 152, 309–344 (in German) (1924).

    CAS  Google Scholar 

  2. 2

    Medes, G., Thomas, A. & Weinhouse, S. Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res. 13, 27–29 (1953). This study was the first to determine lipid synthesis in neoplastic tissues.

    CAS  PubMed  Google Scholar 

  3. 3

    Ookhtens, M., Kannan, R., Lyon, I. & Baker, N. Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am. J. Physiol. 247, R146–R153 (1984).

    CAS  PubMed  Google Scholar 

  4. 4

    Kuhajda, F. P. et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc. Natl Acad. Sci. USA 91, 6379–6383 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. 5

    Santos, C. R. & Schulze, A. Lipid metabolism in cancer. FEBS J. 279, 2610–2623 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. 6

    Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, R. V. Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Shevchenko, A. & Simons, K. Lipidomics: coming to grips with lipid diversity. Nat. Rev. Mol. Cell Biol. 11, 593–598 (2010).

    Article  CAS  Google Scholar 

  8. 8

    Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7, 763–777 (2007).

    Article  CAS  Google Scholar 

  9. 9

    Kusakabe, T. et al. Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells. J. Histochem. Cytochem. 48, 613–622 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Cai, Y. et al. Loss of chromosome 8p governs tumor progression and drug response by altering lipid metabolism. Cancer Cell 29, 751–766 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Zaidi, N., Swinnen, J. V. & Smans, K. ATP-citrate lyase: a key player in cancer metabolism. Cancer Res. 72, 3709–3714 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Brownsey, R. W., Boone, A. N., Elliott, J. E., Kulpa, J. E. & Lee, W. M. Regulation of acetyl-CoA carboxylase. Biochem. Soc. Trans. 34, 223–227 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Maier, T., Leibundgut, M. & Ban, N. The crystal structure of a mammalian fatty acid synthase. Science 321, 1315–1322 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Jakobsson, A., Westerberg, R. & Jacobsson, A. Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog. Lipid Res. 45, 237–249 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Igal, R. A. Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis 31, 1509–1515 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Horton, J. D. Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochem. Soc. Trans. 30, 1091–1095 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Amemiya-Kudo, M. et al. Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes. J. Lipid Res. 43, 1220–1235 (2002).

    CAS  Google Scholar 

  18. 18

    Mullen, P. J., Yu, R., Longo, J., Archer, M. C. & Penn, L. Z. The interplay between cell signaling and the mevalonate pathway in cancer. Nat. Rev. Cancer https://dx.doi.org/10.1038/nrc.2016.76 (2016).

  19. 19

    Shimano, H. et al. Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J. Biol. Chem. 274, 35832–35839 (1999).

    Article  CAS  Google Scholar 

  20. 20

    Shechter, I., Dai, P., Huo, L. & Guan, G. IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells. J. Lipid Res. 44, 2169–2180 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010). This study identified SREBP as a major component of the gene regulatory network downstream of mTORC1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Walker, A. K. et al. A conserved SREBP-1/Phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 147, 840–852 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Nohturfft, A. & Zhang, S. C. Coordination of lipid metabolism in membrane biogenesis. Annu. Rev. Cell Dev. Biol. 25, 539–566 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. 24

    Brown, M. S. & Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331–340 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. 25

    Espenshade, P. J. & Hughes, A. L. Regulation of sterol synthesis in eukaryotes. Annu. Rev. Genet. 41, 401–427 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Fleischmann, M. & Iynedjian, P. B. Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt. Biochem. J. 349, 13–17 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Yang, Y. A., Han, W. F., Morin, P. J., Chrest, F. J. & Pizer, E. S. Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Exp. Cell Res. 279, 80–90 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Porstmann, T. et al. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 24, 6465–6481 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008). This study was the first to demonstrate that SREBP is regulated by mTORC1 and contributes to cell growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Finck, B. N. et al. Lipin 1 is an inducible amplifier of the hepatic PGC-1α/PPARα regulatory pathway. Cell Metab. 4, 199–210 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Peterson, T. R. et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408–420 (2011). This study implicated LPIN1 in the regulation of SREBP by mTORC1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Han, J. et al. The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524, 243–246 (2015). This study showed regulation of SREBP1 processing by mTORC1 through phosphorylation of CRTC2.

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Welcker, M. & Clurman, B. E. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat. Rev. Cancer 8, 83–93 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. 35

    Sundqvist, A. et al. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7). Cell Metab. 1, 379–391 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Bengoechea-Alonso, M. T. & Ericsson, J. A phosphorylation cascade controls the degradation of active SREBP1. J. Biol. Chem. 284, 5885–5895 (2009). References 35 and 36 demonstrated that the stability of mature SREBP is controlled by GSK3β-dependent phosphorylation and ubiquitination by the FBXW7 ubiquitin ligase.

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Dang, C. V. MYC on the path to cancer. Cell 149, 22–35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Tong, X., Zhao, F., Mancuso, A., Gruber, J. J. & Thompson, C. B. The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation. Proc. Natl Acad. Sci. USA 106, 21660–21665 (2009).

    Article  PubMed  Google Scholar 

  39. 39

    Carroll, P. A. et al. Deregulated myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer Cell 27, 271–285 (2015). This study demonstrated that induction of lipid synthesis by MondoA is essential for MYC transformed cells. The effect of MondoA repression was rescued by oleic acid, confirming the importance of monounsaturated FAs for cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Ventura, R. et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine 2, 806–822 (2015).

    Article  Google Scholar 

  41. 41

    Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011).

    Article  PubMed  Google Scholar 

  43. 43

    Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Kamphorst, J. J., Chung, M. K., Fan, J. & Rabinowitz, J. D. Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer Metab. 2, 23 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Kamphorst, J. J. et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc. Natl Acad. Sci. USA 110, 8882–8887 (2013). This study showed that hypoxic or KRAS-transformed cells selectively take up monounsaturated lipids.

    Article  PubMed  Google Scholar 

  46. 46

    Bensaad, K. et al. Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep. 9, 349–365 (2014). This study implicated lipid storage by hypoxic cells in energy provision after reoxygenation.

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Michiels, C., Tellier, C. & Feron, O. Cycling hypoxia: a key feature of the tumor microenvironment. Biochim. Biophys. Acta 1866, 76–86 (2016).

    CAS  PubMed  Google Scholar 

  48. 48

    Yasui, H. et al. Low-field magnetic resonance imaging to visualize chronic and cycling hypoxia in tumor-bearing mice. Cancer Res. 70, 6427–6436 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891–899 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Yue, S. et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 19, 393–406 (2014). This study connected cholesterol esterification to maintain SREBP activity with aggressive behaviour of prostate cancers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Li, J. et al. Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1α. Physiol. Genom. 25, 450–457 (2006).

    Article  CAS  Google Scholar 

  52. 52

    Lewis, C. A. et al. SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme. Oncogene 43, 5128–5140 (2015).

    Article  CAS  Google Scholar 

  53. 53

    Tosi, F., Sartori, F., Guarini, P., Olivieri, O. & Martinelli, N. Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease. Adv. Exp. Med. Biol. 824, 61–81 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Wymann, M. P. & Schneiter, R. Lipid signalling in disease. Nat. Rev. Mol. Cell Biol. 9, 162–176 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Argiles, J. M., Busquets, S., Stemmler, B. & Lopez-Soriano, F. J. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14, 754–762 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    Sonveaux, P. et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 118, 3930–3942 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Romero, I. L., Mukherjee, A., Kenny, H. A., Litchfield, L. M. & Lengyel, E. Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clin. Cancer Res. 21, 680–686 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498–1503 (2011). This study provided an elegant example of metabolic symbiosis of cancer cells and adipocytes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Ye, H. et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell 19, 23–37 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Caiado, F., Silva-Santos, B. & Norell, H. Intra-tumour heterogeneity - going beyond genetics. FEBS J. 283, 2245–2258 (2016).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Schug, Z. T. & Gottlieb, E. Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim. Biophys. Acta 1788, 2022–2031 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Chicco, A. J. & Sparagna, G. C. Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am. J. Physiol. Cell Physiol. 292, C33–44 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    Kiebish, M. A., Han, X., Cheng, H., Chuang, J. H. & Seyfried, T. N. Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer. J. Lipid Res. 49, 2545–2556 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Wallace, D. C. Mitochondria and cancer. Nat. Rev. Cancer 12, 685–698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Mashima, T. et al. p53-defective tumors with a functional apoptosome-mediated pathway: a new therapeutic target. J. Natl Cancer Inst. 97, 765–777 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Potze, L. et al. Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification. Oncogene 35, 427–437 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Peck, B. et al. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments. Cancer Metab. 4, 6 (2016). This study analysed the effect of SCD inhibition on lipid composition and survival in cancer cells. It also demonstrated that SCD silencing efficiently blocks growth of prostate cancer orthografts.

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Schepers, A. & Clevers, H. Wnt signaling, stem cells, and cancer of the gastrointestinal tract. Cold Spring Harb. Perspect. Biol. 4, a007989 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Nile, A. H. & Hannoush, R. N. Fatty acylation of Wnt proteins. Nat. Chem. Biol. 12, 60–69 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Proffitt, K. D. et al. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res. 73, 502–507 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Liu, J. et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl Acad. Sci. USA 110, 20224–20229 (2013).

    Article  CAS  Google Scholar 

  74. 74

    Rios-Esteves, J. & Resh, M. D. Stearoyl CoA desaturase is required to produce active, lipid-modified Wnt proteins. Cell Rep. 4, 1072–1081 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    Kim, H. et al. Unsaturated fatty acids stimulate tumor growth through stabilization of β-catenin. Cell Rep. 13, 496–503 (2015).

    Google Scholar 

  76. 76

    Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer 13, 11–26 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Levental, I., Grzybek, M. & Simons, K. Greasing their way: lipid modifications determine protein association with membrane rafts. Biochemistry 49, 6305–6316 (2010).

    Article  CAS  Google Scholar 

  78. 78

    Pyne, N. J. & Pyne, S. Sphingosine 1-phosphate and cancer. Nat. Rev. Cancer 10, 489–503 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Park, J. B. et al. Phospholipase signalling networks in cancer. Nat. Rev. Cancer 12, 782–792 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Griner, E. M. & Kazanietz, M. G. Protein kinase C and other diacylglycerol effectors in cancer. Nat. Rev. Cancer 7, 281–294 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Vanhaesebroeck, B., Stephens, L. & Hawkins, P. PI3K signalling: the path to discovery and understanding. Nat. Rev. Mol. Cell Biol. 13, 195–203 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Muinonen-Martin, A. J. et al. Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal. PLoS Biol. 12, e1001966 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Choi, J. W. et al. LPA receptors: subtypes and biological actions. Annu. Rev. Pharmacol. Toxicol. 50, 157–186 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    Bandoh, K. et al. Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species. Structure-activity relationship of cloned LPA receptors. FEBS Lett. 478, 159–165 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. 85

    Chan, L. C. et al. LPA3 receptor mediates chemotaxis of immature murine dendritic cells to unsaturated lysophosphatidic acid (LPA). J. Leukoc. Biol. 82, 1193–1200 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Goto, T. et al. The expression profile of phosphatidylinositol in high spatial resolution imaging mass spectrometry as a potential biomarker for prostate cancer. PLoS ONE 9, e90242 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Louie, S. M., Roberts, L. S., Mulvihill, M. M., Luo, K. & Nomura, D. K. Cancer cells incorporate and remodel exogenous palmitate into structural and oncogenic signaling lipids. Biochim. Biophys. Acta 1831, 1566–1572 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    Hilvo, M. et al. Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression. Cancer Res. 71, 3236–3245 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Rysman, E. et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res. 70, 8117–8126 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Wang, D. & Dubois, R. N. Eicosanoids and cancer. Nat. Rev. Cancer 10, 181–193 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Pan, Y. et al. Deletion of cyclooxygenase-2 inhibits K-ras-induced lung carcinogenesis. Oncotarget 6, 38816–38826 (2015).

    PubMed  PubMed Central  Google Scholar 

  92. 92

    Howe, L. R. et al. HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. Cancer Res. 65, 10113–10119 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Sonoshita, M. et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ 716 knockout mice. Nat. Med. 7, 1048–1051 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    Wang, D., Buchanan, F. G., Wang, H., Dey, S. K. & DuBois, R. N. Prostaglandin E2 enhances intestinal adenoma growth via activation of the Ras-mitogen-activated protein kinase cascade. Cancer Res. 65, 1822–1829 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    Castellone, M. D., Teramoto, H., Williams, B. O., Druey, K. M. & Gutkind, J. S. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-β-catenin signaling axis. Science 310, 1504–1510 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015). This study demonstrated the role of prostaglandin synthesis in the suppression of myeloid cell activation and immune evasion in melanoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    De Craene, B. & Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13, 97–110 (2013).

    Article  CAS  Google Scholar 

  98. 98

    Vo, B. T. et al. TGF-β effects on prostate cancer cell migration and invasion are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway. Endocrinology 154, 1768–1779 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Jiang, L. et al. Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition. Oncogene 34, 3908–3916 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Nath, A., Li, I., Roberts, L. R. & Chan, C. Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci. Rep. 5, 14752 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Rahaman, S. O. et al. A CD36-dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab. 4, 211–221 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Zhao, W. et al. Candidate anti-metastasis drugs suppress the metastatic capacity of breast cancer cells by reducing membrane fluidity. Cancer Res. 76, 2037–2049 (2016).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Folkman, J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29, 15–18 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Kazlauskas, A. Lysophosphatidic acid contributes to angiogenic homeostasis. Exp. Cell Res. 333, 166–170 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Mendelson, K., Evans, T. & Hla, T. Sphingosine 1-phosphate signalling. Development 141, 5–9 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192–197 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Forootan, F. S. et al. Fatty acid activated PPARγ promotes tumorigenicity of prostate cancer cells by up regulating VEGF via PPAR responsive elements of the promoter. Oncotarget 7, 9322–9339 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Teng, M. W., Galon, J., Fridman, W. H. & Smyth, M. J. From mice to humans: developments in cancer immunoediting. J. Clin. Invest. 125, 3338–3346 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Kalinski, P. Regulation of immune responses by prostaglandin E2. J. Immunol. 188, 21–28 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Luan, B. et al. CREB pathway links PGE2 signaling with macrophage polarization. Proc. Natl Acad. Sci. USA 112, 15642–15647 (2015).

    CAS  PubMed  Google Scholar 

  111. 111

    Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015). This study provided evidence of the competition between cancer cells and immune cells for nutrients within the tumour microenvironment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Wang, R. & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Baginska, J. et al. The critical role of the tumor microenvironment in shaping natural killer cell-mediated anti-tumor immunity. Front. Immunol. 4, 490 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Kleinfeld, A. M. & Okada, C. Free fatty acid release from human breast cancer tissue inhibits cytotoxic T-lymphocyte-mediated killing. J. Lipid Res. 46, 1983–1990 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Ma, C. et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Kinlaw, W. B., Baures, P. W., Lupien, L. E., Davis, W. L. & Kuemmerle, N. B. Fatty acids and breast cancer: make them on site or have them delivered. J. Cell. Physiol. 231, 2128–2141 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Flavin, R., Zadra, G. & Loda, M. Metabolic alterations and targeted therapies in prostate cancer. J. Pathol. 223, 283–294 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Pizer, E. S. et al. Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res. 56, 1189–1193 (1996).

    CAS  PubMed  Google Scholar 

  119. 119

    Pizer, E. S. et al. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res. 60, 213–218 (2000).

    CAS  PubMed  Google Scholar 

  120. 120

    Menendez, J. A. et al. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Natl Acad. Sci. USA 101, 10715–10720 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. 121

    Pizer, E. S., Chrest, F. J., DiGiuseppe, J. A. & Han, W. F. Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res. 58, 4611–4615 (1998).

    CAS  PubMed  Google Scholar 

  122. 122

    Li, J. N. et al. Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res. 61, 1493–1499 (2001).

    CAS  PubMed  Google Scholar 

  123. 123

    Zhou, W. et al. Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. Cancer Res. 63, 7330–7337 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Menendez, J. A., Vellon, L., Colomer, R. & Lupu, R. Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity. Int. J. Cancer 115, 19–35 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. 125

    Gabrielson, E. W., Pinn, M. L., Testa, J. R. & Kuhajda, F. P. Increased fatty acid synthase is a therapeutic target in mesothelioma. Clin. Cancer Res. 7, 153–157 (2001).

    CAS  PubMed  Google Scholar 

  126. 126

    Horiguchi, A. et al. Pharmacological inhibitor of fatty acid synthase suppresses growth and invasiveness of renal cancer cells. J. Urol. 180, 729–736 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. 127

    Relat, J. et al. Different fatty acid metabolism effects of (-)-epigallocatechin-3-gallate and C75 in adenocarcinoma lung cancer. BMC Cancer 12, 280 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Chen, H. W., Chang, Y. F., Chuang, H. Y., Tai, W. T. & Hwang, J. J. Targeted therapy with fatty acid synthase inhibitors in a human prostate carcinoma LNCaP/tk-luc-bearing animal model. Prostate Cancer Prostat. Dis. 15, 260–264 (2012).

    Article  CAS  Google Scholar 

  129. 129

    Alli, P. M., Pinn, M. L., Jaffee, E. M., McFadden, J. M. & Kuhajda, F. P. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 24, 39–46 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. 130

    Wang, X. & Tian, W. Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase. Biochem. Biophys. Res. Commun. 288, 1200–1206 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Loftus, T. M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379–2381 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. 132

    Shimokawa, T., Kumar, M. V. & Lane, M. D. Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc. Natl Acad. Sci. USA 99, 66–71 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. 133

    Cha, S. H., Hu, Z., Chohnan, S. & Lane, M. D. Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle. Proc. Natl Acad. Sci. USA 102, 14557–14562 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. 134

    Li, L. et al. Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans. J. Hepatol. 64, 333–341 (2016).

    Article  CAS  PubMed  Google Scholar 

  135. 135

    Knobloch, M. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230 (2013). This study demonstrated that FASN is highly active in proliferating adult neural stem cell progenitors.

    Article  CAS  PubMed  Google Scholar 

  136. 136

    Bauer, D. E., Hatzivassiliou, G., Zhao, F., Andreadis, C. & Thompson, C. B. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24, 6314–6322 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. 137

    Zaidi, N., Royaux, I., Swinnen, J. V. & Smans, K. ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms. Mol. Cancer Ther. 11, 1925–1935 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. 138

    Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Schug, Z. T. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57–71 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591–1602 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Yoshii, Y. et al. Cytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism. Cancer Sci. 100, 821–827 (2009).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603–1614 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Schug, Z. T., Vande Voorde, J. & Gottlieb, E. Metabolic fate of acetate in cancer. Nat. Rev. Cancer https://dx.doi.org/10.1038/nrc.2016.87 (2016).

  144. 144

    Wang, C. et al. Acetyl-CoA carboxylase-α inhibitor TOFA induces human cancer cell apoptosis. Biochem. Biophys. Res. Commun. 385, 302–306 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Brusselmans, K., De Schrijver, E., Verhoeven, G. & Swinnen, J. V. RNA interference-mediated silencing of the acetyl-CoA-carboxylase-α gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res. 65, 6719–6725 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. 146

    Chajes, V., Cambot, M., Moreau, K., Lenoir, G. M. & Joulin, V. Acetyl-CoA carboxylase α is essential to breast cancer cell survival. Cancer Res. 66, 5287–5294 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. 147

    Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Griffiths, B. et al. Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer Metab. 1, 3 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Williams, K. J. et al. An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. Cancer Res. 73, 2850–2862 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Young, R. M. et al. Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes Dev. 27, 1115–1131 (2013). References 148–150 demonstrated that inhibition of FA desaturation leads to the induction of ER stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Sanchez-Alvarez, M. et al. Signaling networks converge on TORC1-SREBP activity to promote endoplasmic reticulum homeostasis. PLoS ONE 9, e101164 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Guo, D. et al. EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci. Signal. 2, ra82 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Cheng, C. et al. Glucose-mediated N-glycosylation of SCAP is essential for SREBP-1 activation and tumor growth. Cancer Cell 28, 569–581 (2015). This study provided mechanistic evidence for SREBP activation in glycolytic cancer cells through enhanced glycosylation of SCAP. It also demonstrated that SCAP depletion reduces orthotopic glioblastoma growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Zelcer, N., Hong, C., Boyadjian, R. & Tontonoz, P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325, 100–104 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Bovenga, F., Sabba, C. & Moschetta, A. Uncoupling nuclear receptor LXR and cholesterol metabolism in cancer. Cell Metab. 21, 517–526 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. 156

    Guo, D. et al. An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 1, 442–456 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Flaveny, C. A. et al. Broad anti-tumor activity of a small molecule that selectively targets the warburg effect and lipogenesis. Cancer Cell 28, 42–56 (2015). This study showed that inhibition of SREBP by an LXR antagonist blocks glycolysis and lipogenesis in cancer cells and inhibits tumour cell growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Kamisuki, S. et al. A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem. Biol. 16, 882–892 (2009).

    Article  CAS  Google Scholar 

  159. 159

    Li, X., Chen, Y. T., Hu, P. & Huang, W. C. Fatostatin displays high antitumor activity in prostate cancer by blocking SREBP-regulated metabolic pathways and androgen receptor signaling. Mol. Cancer Ther. 13, 855–866 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Li, X., Wu, J. B., Chung, L. W. & Huang, W. C. Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations. Oncotarget 6, 41018–41032 (2015).

    PubMed  PubMed Central  Google Scholar 

  161. 161

    Tang, J. J. et al. Inhibition of SREBP by a small molecule, betulin, improves hyperlipidemia and insulin resistance and reduces atherosclerotic plaques. Cell Metab. 13, 44–56 (2011).

    CAS  Google Scholar 

  162. 162

    Krol, S. K., Kielbus, M., Rivero-Muller, A. & Stepulak, A. Comprehensive review on betulin as a potent anticancer agent. Biomed. Res. Int. 2015, 584189 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Matsuda, M. et al. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev. 15, 1206–1216 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Winter, G. E. et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Marien, E. et al. Phospholipid profiling identifies acyl chain elongation as a ubiquitous trait and potential target for the treatment of lung squamous cell carcinoma. Oncotarget 7, 12582–12597 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  166. 166

    Mason, P. et al. SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids. PLoS ONE 7, e33823 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Hess, D., Chisholm, J. W. & Igal, R. A. Inhibition of stearoylCoA desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells. PLoS ONE 5, e11394 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Roongta, U. V. et al. Cancer cell dependence on unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy. Mol. Cancer Res. 9, 1551–1561 (2011).

    Article  CAS  PubMed  Google Scholar 

  170. 170

    Fritz, V. et al. Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice. Mol. Cancer Ther. 9, 1740–1754 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Scaglia, N. & Igal, R. A. Inhibition of Stearoyl-CoA Desaturase 1 expression in human lung adenocarcinoma cells impairs tumorigenesis. Int. J. Oncol. 33, 839–850 (2008).

    CAS  PubMed  Google Scholar 

  172. 172

    Budhu, A. et al. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology 144, 1066–1075 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Menendez, J. A., Lupu, R. & Colomer, R. Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER-2/neu-overexpressing human breast cancer cells to docetaxel (taxotere). Breast Cancer Res. Treat. 84, 183–195 (2004).

    Article  CAS  PubMed  Google Scholar 

  175. 175

    Vazquez-Martin, A., Ropero, S., Brunet, J., Colomer, R. & Menendez, J. A. Inhibition of Fatty Acid Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells. Oncol. Rep. 18, 973–980 (2007).

    CAS  PubMed  Google Scholar 

  176. 176

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

    Article  CAS  PubMed  Google Scholar 

  177. 177

    Ebos, J. M. & Kerbel, R. S. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210–221 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Sounni, N. E. et al. Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab. 20, 280–294 (2014). This study suggested that inhibition of lipid synthesis may prevent disease progression following antiangiogenic therapy.

    Article  CAS  PubMed  Google Scholar 

  179. 179

    Golay, A., Swislocki, A. L., Chen, Y. D., Jaspan, J. B. & Reaven, G. M. Effect of obesity on ambient plasma glucose, free fatty acid, insulin, growth hormone, and glucagon concentrations. J. Clin. Endocrinol. Metab. 63, 481–484 (1986).

    Article  CAS  PubMed  Google Scholar 

  180. 180

    Lewis, D. Y. et al. Late imaging with [1-11C]Acetate improves detection of tumor fatty acid synthesis with PET. J. Nucl. Med. 55, 1144–1149 (2014).

    Article  CAS  PubMed  Google Scholar 

  181. 181

    DeGrado, T. R., Kitapci, M. T., Wang, S., Ying, J. & Lopaschuk, G. D. Validation of 18F-fluoro-4-thia-palmitate as a PET probe for myocardial fatty acid oxidation: effects of hypoxia and composition of exogenous fatty acids. J. Nucl. Med. 47, 173–181 (2006).

    CAS  PubMed  Google Scholar 

  182. 182

    Krahmer, N., Guo, Y., Farese, R. V. Jr & Walther, T. C. SnapShot: lipid droplets. Cell 139, 1024–1024.e1 (2009).

    Article  CAS  PubMed  Google Scholar 

  183. 183

    Zechner, R. FAT FLUX: enzymes, regulators, and pathophysiology of intracellular lipolysis. EMBO Mol. Med. 7, 359–362 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Vamecq, J., Cherkaoui-Malki, M., Andreoletti, P. & Latruffe, N. The human peroxisome in health and disease: the story of an oddity becoming a vital organelle. Biochimie 98, 4–15 (2014).

    Article  CAS  PubMed  Google Scholar 

  185. 185

    Carling, D., Clarke, P. R., Zammit, V. A. & Hardie, D. G. Purification and characterization of the AMP-activated protein kinase. Copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities. Eur. J. Biochem. 186, 129–136 (1989).

    Article  CAS  PubMed  Google Scholar 

  186. 186

    Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13, 227–232 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Park, J. H. et al. Fatty acid oxidation-driven src links mitochondrial energy reprogramming and oncogenic properties in triple-negative breast cancer. Cell Rep. 14, 2154–2165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Szutowicz, A., Kwiatkowski, J. & Angielski, S. Lipogenetic and glycolytic enzyme activities in carcinoma and nonmalignant diseases of the human breast. Br. J. Cancer 39, 681–687 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Hietanen, E., Punnonen, K., Punnonen, R. & Auvinen, O. Fatty acid composition of phospholipids and neutral lipids and lipid peroxidation in human breast cancer and lipoma tissue. Carcinogenesis 7, 1965–1969 (1986).

    Article  CAS  PubMed  Google Scholar 

  191. 191

    Yokoyama, C. et al. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75, 187–197 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Hua, X. et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc. Natl Acad. Sci. USA 90, 11603–11607 (1993).

    Article  CAS  PubMed  Google Scholar 

  193. 193

    Tontonoz, P., Kim, J. B., Graves, R. A. & Spiegelman, B. M. ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation. Mol. Cell. Biol. 13, 4753–4759 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. 194

    Bennett, M. K., Lopez, J. M., Sanchez, H. B. & Osborne, T. F. Sterol regulation of fatty acid synthase promoter. Coordinate feedback regulation of two major lipid pathways. J. Biol. Chem. 270, 25578–25583 (1995).

    Article  CAS  PubMed  Google Scholar 

  195. 195

    Swinnen, J. V., Esquenet, M., Goossens, K., Heyns, W. & Verhoeven, G. Androgens stimulate fatty acid synthase in the human prostate cancer cell line LNCaP. Cancer Res. 57, 1086–1090 (1997).

    CAS  PubMed  Google Scholar 

  196. 196

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02223247 (2014).

  198. 198

    Buckley, D., Heuer, T., O'Farrell, M., McCulloch, B. & Kemble, G. Translational studies of a first-in-class FASN Inhibitor, TVB-2640, linking preclinical studies to clinical laboratory observations in solid tumor patients. Mol. Cancer Res. 14 (Suppl. 1), Abstr. A75 (2016).

    Google Scholar 

  199. 199

    Shaw, G. et al. Therapeutic fatty acid synthase inhibition in prostate cancer and the use of 11c-acetate to monitor therapeutic effects. J. Urol. 189, E208–E209 (2013).

    Google Scholar 

  200. 200

    Zhou, W. et al. Fatty acid synthase inhibition activates AMP-activated protein kinase in SKOV3 human ovarian cancer cells. Cancer Res. 67, 2964–2971 (2007).

    Article  CAS  PubMed  Google Scholar 

  201. 201

    Orita, H. et al. Selective inhibition of fatty acid synthase for lung cancer treatment. Clin. Cancer Res. 13, 7139–7145 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202

    El Meskini, R. et al. Fatty acid synthase inhibition for ovarian cancer. Cancer Res. 68, Supplement 5667 http://cancerres.aacrjournals.org/content/68/9_Supplement/5667 (2008).

  203. 203

    Orita, H. et al. Inhibition of fatty acid synthase by C247 for lung cancer treatment. Cancer Res. 65, Supplement 2380 http://cancerres.aacrjournals.org/content/65/9_Supplement/558.2 (2005).

  204. 204

    Pizer, E. S. et al. Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res. 56, 2745–2747 (1996).

    CAS  PubMed  Google Scholar 

  205. 205

    Kridel, S. J., Axelrod, F., Rozenkrantz, N. & Smith, J. W. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64, 2070–2075 (2004).

    Article  CAS  PubMed  Google Scholar 

  206. 206

    Carvalho, M. A. et al. Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model. Int. J. Cancer 123, 2557–2565 (2008).

    Article  CAS  PubMed  Google Scholar 

  207. 207

    Sadowski, M. C. et al. The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer. Oncotarget 5, 9362–9381 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  208. 208

    Lee, H. R., Hwang, K. A., Nam, K. H., Kim, H. C. & Choi, K. C. Progression of breast cancer cells was enhanced by endocrine-disrupting chemicals, triclosan and octylphenol, via an estrogen receptor-dependent signaling pathway in cellular and mouse xenograft models. Chem. Res. Toxicol. 27, 834–842 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. 209

    Beckers, A. et al. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res. 67, 8180–8187 (2007).

    Article  CAS  PubMed  Google Scholar 

  210. 210

    Samudio, I. et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J. Clin. Invest. 120, 142–156 (2010).

    Article  CAS  PubMed  Google Scholar 

  211. 211

    Tirado-Velez, J. M., Joumady, I., Saez-Benito, A., Cozar-Castellano, I. & Perdomo, G. Inhibition of fatty acid metabolism reduces human myeloma cells proliferation. PLoS ONE 7, e46484 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. 212

    Liu, P. P. et al. Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline. Oncogene https://dx.doi.org/10.1038/onc.2016.103 (2016).

  213. 213

    Von Roemeling, C. A. et al. Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Clin. Cancer Res. 19, 2368–2380 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank B. Peck for helpful discussions and all members of the Schulze laboratory for critical reading of the manuscript. We also wish to apologize for the numerous important studies in the field of lipid metabolism in cancer that we could not cite owing to space limitations.

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Correspondence to Almut Schulze.

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Glossary

Fatty acid synthase

(FASN). Mammalian FASN is a multifunctional enzyme containing seven catalytic domains: malonyl/acetyltransferase, β-ketoacyl-synthase, dehydrase, enoyl-ACP-reductase, β-ketoacyl-reductase, thioesterase and acyl carrier protein.

β-Oxidation

The process by which fatty acids are sequentially degraded to acetyl-CoA, which can subsequently be oxidized by the mitochondrial tricarboxylic acid cycle to produce ATP.

E-Box sequences

Palindromic DNA element with the consensus sequence CANNTG, which is found in the promoters of many genes and mediates transcription factor binding.

Lipid droplets

Specialized organelles rich in neutral lipids, cholesterol and cholesteryl esters.

Lipid rafts

Highly specialized microdomains in the plasma membrane characterized by distinct lipid composition that act as platforms for the assembly of signalling molecules.

Raman spectroscopy

A label-free spectroscopic imaging technique that can be applied to tissue sections. It is based on a characteristic shift in the frequency of light used to illuminate a specimen.

Cachexia

Wasting syndrome characterized by atrophy of muscle and adipose tissue and extreme weight loss.

Acylation

Post-translational covalent attachment of fatty acids to amino acid side-chains of proteins. Common examples are myristoylation and palmitoylation to promote membrane association of proteins.

WNT proteins

A family of secreted glycoproteins involved in tissue homeostasis and organ development. One pathway activated by WNT proteins is β-catenin-induced transcription.

Epithelial-to-mesenchymal transition

(EMT). A phenotype that occurs during development as well as in cancer cells. During EMT, epithelial cells acquire mesenchymal traits, including loss of cell–cell contacts and enhanced motility, caused by altered transcription and microRNA regulation of cytoskeletal proteins.

Non-alcoholic fatty liver disease

(NAFLD). Pathological accumulation of fat in the liver often associated with insulin resistance and the metabolic syndrome.

Metronomic treatment regimens

Therapeutic concept describing the continuous administration of drugs at doses below the maximum tolerated dose.

Unfolded protein response (UPR) pathway

A stress response pathway activated upon accumulation of misfolded proteins in the lumen of the endoplasmic reticulum.

Imaging mass spectrometry

(IMS). Technique to visualize the spatial distribution of metabolites, biomarkers or proteins in a biological sample, such as a tissue section.

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Röhrig, F., Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer 16, 732–749 (2016). https://doi.org/10.1038/nrc.2016.89

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