The multifaceted roles of fatty acid synthesis in cancer

Nature Reviews Cancer

Volumn 16, Issue 11, 2016, Pages 732-749

  Röhrig, Florian ^a,b   Schulze, Almut ^a,b  

^a UNIVERSITY OF WÜRZBURG   (Germany)

^b Comprehensive Cancer Center Mainfranken ^*  (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CARDIOLIPIN; ICOSANOID; STEROL REGULATORY ELEMENT BINDING PROTEIN; FATTY ACID;

ACYLATION; ANGIOGENESIS; BIOSYNTHESIS; CANCER CELL; CANCER GROWTH; CANCER THERAPY; CARCINOGENESIS; CELL INVASION; CELL MIGRATION; CLINICAL PRACTICE; DISEASE COURSE; FATTY ACID DESATURATION; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; FATTY ACID TRANSPORT; HUMAN; HYPOXIA; IMMUNOSURVEILLANCE; LIPID PEROXIDATION; MALIGNANT NEOPLASTIC DISEASE; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW; SYMBIOSIS; TUMOR GROWTH; TUMOR MICROENVIRONMENT; LIPID METABOLISM; METABOLISM; NEOPLASM; PHYSIOLOGY;

CARCINOGENESIS; DISEASE PROGRESSION; FATTY ACIDS; HUMANS; LIPID METABOLISM; NEOPLASMS; STEROL REGULATORY ELEMENT BINDING PROTEINS; TUMOR MICROENVIRONMENT;

EID: 84988553080     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc.2016.89     Document Type: Review

References (213)

1. Warburg, O., Posener, K., & Negelein, E. Über den Stoffwechsel Der Carcinomzelle. Biochem. Zeitschr. 152, 309-344 (in German) (1924
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
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
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
5. Santos, C. R., & Schulze, A. Lipid metabolism in cancer. FEBS J. 279, 2610-2623 (2012
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
7. Shevchenko, A., & Simons, K. Lipidomics: coming to grips with lipid diversity. Nat. Rev. Mol. Cell Biol. 11, 593-598 (2010
8. Menendez, J. A., & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7, 763-777 (2007
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
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
11. Zaidi, N., Swinnen, J. V., & Smans, K. ATP-citrate lyase: a key player in cancer metabolism. Cancer Res. 72, 3709-3714 (2012
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
13. Maier, T., Leibundgut, M., & Ban, N. The crystal structure of a mammalian fatty acid synthase. Science 321, 1315-1322 (2008
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
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
16. Horton, J. D. Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochem. Soc. Trans. 30, 1091-1095 (2002
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
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. 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
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
21. Duvel, K., et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171-183 (2010
22. Walker, A. K., et al. A conserved SREBP 1/Phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 147, 840-852 (2011
23. Nohturfft, A., & Zhang, S. C. Coordination of lipid metabolism in membrane biogenesis. Annu. Rev. Cell Dev. Biol. 25, 539-566 (2009
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
25. Espenshade, P. J., & Hughes, A. L. Regulation of sterol synthesis in eukaryotes. Annu. Rev. Genet. 41, 401-427 (2007
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
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
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
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
30. Porstmann, T., et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224-236 (2008
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
32. Peterson, T. R., et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408-420 (2011
33. Han, J., et al. The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524, 243-246 (2015
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
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
36. Bengoechea-Alonso, M. T., & Ericsson, J. A phosphorylation cascade controls the degradation of active SREBP1. J. Biol. Chem. 284, 5885-5895 (2009
37. Dang, C. V. MYC on the path to cancer. Cell 149, 22-35 (2012
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
39. Carroll, P. A., et al. Deregulated myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer Cell 27, 271-285 (2015
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
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
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
43. Metallo, C. M., et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380-384 (2011
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
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
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
47. Michiels, C., Tellier, C., & Feron, O. Cycling hypoxia: a key feature of the tumor microenvironment. Biochim. Biophys. Acta 1866, 76-86 (2016
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
49. Gatenby, R. A., & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891-899 (2004
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
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
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
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
54. Wymann, M. P., & Schneiter, R. Lipid signalling in disease. Nat. Rev. Mol. Cell Biol. 9, 162-176 (2008
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
56. Sonveaux, P., et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 118, 3930-3942 (2008
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
58. Nieman, K. M., et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498-1503 (2011
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
60. Caiado, F., Silva-Santos, B., & Norell, H. Intra-tumour heterogeneity -going beyond genetics. FEBS J. 283, 2245-2258 (2016
61. Hatzivassiliou, G., et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311-321 (2005
62. Schug, Z. T., & Gottlieb, E. Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim. Biophys. Acta 1788, 2022-2031 (2009
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
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
65. Warburg, O. On the origin of cancer cells. Science 123, 309-314 (1956
66. Wallace, D. C. Mitochondria and cancer. Nat. Rev. Cancer 12, 685-698 (2012
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
68. Potze, L., et al. Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification. Oncogene 35, 427-437 (2015
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
70. Schepers, A., & Clevers, H. Wnt signaling, stem cells, and cancer of the gastrointestinal tract. Cold Spring Harb. Perspect. Biol. 4, a007989 (2012
71. Nile, A. H., & Hannoush, R. N. Fatty acylation of Wnt proteins. Nat. Chem. Biol. 12, 60-69 (2016
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
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
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
75. Kim, H., et al. Unsaturated fatty acids stimulate tumor growth through stabilization of β-catenin. Cell Rep. 13, 496-503 (2015
76. Anastas, J. N., & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer 13, 11-26 (2013
77. Levental, I., Grzybek, M., & Simons, K. Greasing their way: lipid modifications determine protein association with membrane rafts. Biochemistry 49, 6305-6316 (2010
78. Pyne, N. J., & Pyne, S. Sphingosine 1 phosphate and cancer. Nat. Rev. Cancer 10, 489-503 (2010
79. Park, J. B., et al. Phospholipase signalling networks in cancer. Nat. Rev. Cancer 12, 782-792 (2012
80. Griner, E. M., & Kazanietz, M. G. Protein kinase C and other diacylglycerol effectors in cancer. Nat. Rev. Cancer 7, 281-294 (2007
81. Vanhaesebroeck, B., Stephens, L., & Hawkins, P. PI3K signalling: the path to discovery and understanding. Nat. Rev. Mol. Cell Biol. 13, 195-203 (2012
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
83. Choi, J. W., et al. LPA receptors: subtypes and biological actions. Annu. Rev. Pharmacol. Toxicol. 50, 157-186 (2010
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
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
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
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
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
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
90. Wang, D., & Dubois, R. N. Eicosanoids and cancer. Nat. Rev. Cancer 10, 181-193 (2010
91. Pan, Y., et al. Deletion of cyclooxygenase 2 inhibits K ras-induced lung carcinogenesis. Oncotarget 6, 38816-38826 (2015
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
93. Sonoshita, M., et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apcδ 716 knockout mice. Nat. Med. 7, 1048-1051 (2001
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
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
96. Zelenay, S., et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257-1270 (2015
97. De Craene, B., & Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13, 97-110 (2013
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
99. Jiang, L., et al. Metabolic reprogramming during TGFβ1 induced epithelial-to mesenchymal transition. Oncogene 34, 3908-3916 (2015
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
101. Rahaman, S. O., et al. A CD36 dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab. 4, 211-221 (2006
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
103. Folkman, J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29, 15-18 (2002
104. Kazlauskas, A. Lysophosphatidic acid contributes to angiogenic homeostasis. Exp. Cell Res. 333, 166-170 (2015
105. Mendelson, K., Evans, T., & Hla, T. Sphingosine 1 phosphate signalling. Development 141, 5-9 (2014
106. Schoors, S., et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192-197 (2015
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
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
109. Kalinski, P. Regulation of immune responses by prostaglandin E2. J. Immunol. 188, 21-28 (2012
110. Luan, B., et al. CREB pathway links PGE2 signaling with macrophage polarization. Proc. Natl Acad. Sci. USA 112, 15642-15647 (2015
111. Chang, C. H., et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229-1241 (2015
112. Wang, R., & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907-915 (2012
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
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
115. Ma, C., et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253-257 (2016
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
117. Flavin, R., Zadra, G., & Loda, M. Metabolic alterations and targeted therapies in prostate cancer. J. Pathol. 223, 283-294 (2011
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
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
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
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
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
123. Zhou, W., et al. Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. Cancer Res. 63, 7330-7337 (2003
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
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
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
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
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
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
130. Wang, X., & Tian, W. Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase. Biochem. Biophys. Res. Commun. 288, 1200-1206 (2001
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
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
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
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
135. Knobloch, M., et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226-230 (2013
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
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
138. Wellen, K. E., et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076-1080 (2009
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
140. Comerford, S. A., et al. Acetate dependence of tumors. Cell 159, 1591-1602 (2014
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
142. Mashimo, T., et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603-1614 (2014
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. Wang, C., et al. Acetyl-CoA carboxylase-α inhibitor TOFA induces human cancer cell apoptosis. Biochem. Biophys. Res. Commun. 385, 302-306 (2009
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
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
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
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
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
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
151. Sanchez-Alvarez, M., et al. Signaling networks converge on TORC1 SREBP activity to promote endoplasmic reticulum homeostasis. PLoS ONE 9, e101164 (2014
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
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
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
155. Bovenga, F., Sabba, C., & Moschetta, A. Uncoupling nuclear receptor LXR and cholesterol metabolism in cancer. Cell Metab. 21, 517-526 (2015
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
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
158. Kamisuki, S., et al. A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem. Biol. 16, 882-892 (2009
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
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
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
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
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
164. Winter, G. E., et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376-1381 (2015
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
166. Mason, P., et al. SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids. PLoS ONE 7, e33823 (2012
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
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
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
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
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
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
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
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
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
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
177. Ebos, J. M., & Kerbel, R. S. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210-221 (2011
178. Sounni, N. E., et al. Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab. 20, 280-294 (2014
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
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
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
182. Krahmer, N., Guo, Y., Farese, R. V. Jr, & Walther, T. C. SnapShot: lipid droplets. Cell 139, 1024-1024.e1 (2009
183. Zechner, R. FAT FLUX: enzymes, regulators, and pathophysiology of intracellular lipolysis. EMBO Mol. Med. 7, 359-362 (2015
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
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
186. Carracedo, A., Cantley, L. C., & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13, 227-232 (2013
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
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
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
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
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
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
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
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
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
196. Hanahan, D., & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011
197. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02223247 (2014
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
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
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
201. Orita, H., et al. Selective inhibition of fatty acid synthase for lung cancer treatment. Clin. Cancer Res. 13, 7139-7145 (2007
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. 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. 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
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
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
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
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
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
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
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
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. 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