Skip to main content
Medline Book to support NIHPA logoLink to Medline Book to support NIHPA
. 2021;1311:39–56. doi: 10.1007/978-3-030-65768-0_3

The Heterogeneity of Lipid Metabolism in Cancer.

Joshua K Park, Nathan J Coffey, Aaron Limoges, Anne Le
PMCID: PMC9703268  PMID: 34014533

Abstract

The study of cancer cell metabolism has traditionally focused on glycolysis and glutaminolysis. However, lipidomic technologies have matured considerably over the last decade and broadened our understanding of how lipid metabolism is relevant to cancer biology [1-3]. Studies now suggest that the reprogramming of cellular lipid metabolism contributes directly to malignant transformation and progression [4, 5]. For example, de novo lipid synthesis can supply proliferating tumor cells with phospholipid components that comprise the plasma and organelle membranes of new daughter cells [6, 7]. Moreover, the upregulation of mitochondrial β-oxidation can support tumor cell energetics and redox homeostasis [8], while lipid-derived messengers can regulate major signaling pathways or coordinate immunosuppressive mechanisms [9-11]. Lipid metabolism has, therefore, become implicated in a variety of oncogenic processes, including metastatic colonization, drug resistance, and cell differentiation [10, 12-16]. However, whether we can safely and effectively modulate the underlying mechanisms of lipid metabolism for cancer therapy is still an open question.


Full text of this article can be found in Bookshelf.

References

  1. Ma, X., et al. (2016). Identification and quantitation of lipid C=C location isomers: A shotgun lipidomics approach enabled by photochemical reaction. Proceedings of the National Academy of Sciences, 113(10), 2573–2578. doi: 10.1073/pnas.1523356113. [DOI] [PMC free article] [PubMed]
  2. Shevchenko, A., & Simons, K. (2010). Lipidomics: Coming to grips with lipid diversity. Nature Reviews Molecular Cell Biology, 11, 593. doi: 10.1038/nrm2934. [DOI] [PubMed]
  3. Yang, K., & Han, X. (2016). Lipidomics: Techniques, applications, and outcomes related to biomedical sciences. Trends in Biochemical Sciences, 41(11), 954–969. doi: 10.1016/j.tibs.2016.08.010. [DOI] [PMC free article] [PubMed]
  4. DeBerardinis, R. J., & Chandel, N. S. (2016). Fundamentals of cancer metabolism. Science Advances, 2(5), e1600200. doi: 10.1126/sciadv.1600200. [DOI] [PMC free article] [PubMed]
  5. Beloribi-Djefaflia, S., Vasseur, S., & Guillaumond, F. (2016). Lipid metabolic reprogramming in cancer cells. Oncogene, 5, e189. doi: 10.1038/oncsis.2015.49. [DOI] [PMC free article] [PubMed]
  6. Zalba, S., & ten Hagen, T. L. M. (2017). Cell membrane modulation as adjuvant in cancer therapy. Cancer Treatment Reviews, 52, 48–57. doi: 10.1016/j.ctrv.2016.10.008. [DOI] [PMC free article] [PubMed]
  7. Rysman, E., et al. (2010). De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Research, 70(20), 8117–8126. doi: 10.1158/0008-5472.CAN-09-3871. [DOI] [PubMed]
  8. Jeon, S.-M., Chandel, N. S., & Hay, N. (2012). AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature, 485, 661. doi: 10.1038/nature11066. [DOI] [PMC free article] [PubMed]
  9. Ayala, A., et al. (2014). Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Medicine and Cellular Longevity, 2014, 31. doi: 10.1155/2014/360438. [DOI] [PMC free article] [PubMed]
  10. Keckesova, Z., et al. (2017). LACTB is a tumour suppressor that modulates lipid metabolism and cell state. Nature, 543, 681. doi: 10.1038/nature21408. [DOI] [PMC free article] [PubMed]
  11. Wang, D., & Dubois, R. N. (2010). Eicosanoids and cancer. Nature Reviews Cancer, 10(3), 181–193. doi: 10.1038/nrc2809. [DOI] [PMC free article] [PubMed]
  12. Pascual, G., et al. (2016). Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature, 541, 41. doi: 10.1038/nature20791. [DOI] [PubMed]
  13. Viswanathan, V. S., et al. (2017). Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature, 547, 453. doi: 10.1038/nature23007. [DOI] [PMC free article] [PubMed]
  14. Luo, X., et al. (2017). Emerging roles of lipid metabolism in cancer metastasis. Molecular Cancer, 16, 76. doi: 10.1186/s12943-017-0646-3. [DOI] [PMC free article] [PubMed]
  15. Hendrich, A. B., & Michalak, K. (2003). Lipids as a target for drugs modulating multidrug resistance of cancer cells. Current Drug Targets, 4(1), 23–30. doi: 10.2174/1389450033347172. [DOI] [PubMed]
  16. Tadros, S., et al. (2017). De novo lipid synthesis facilitates gemcitabine resistance through endoplasmic reticulum stress in pancreatic cancer. Cancer Research, 77(20), 5503–5517. doi: 10.1158/0008-5472.CAN-16-3062. [DOI] [PMC free article] [PubMed]
  17. Ellsworth, R. E., et al. (2017). Molecular heterogeneity in breast cancer: State of the science and implications for patient care. Seminars in Cell & Developmental Biology, 64, 65–72. doi: 10.1016/j.semcdb.2016.08.025. [DOI] [PubMed]
  18. Greaves, M. (2015). Evolutionary determinants of cancer. Cancer Discovery, 5(8), 806–820. doi: 10.1158/2159-8290.CD-15-0439. [DOI] [PMC free article] [PubMed]
  19. Dang, C. V., et al. (2011). Therapeutic targeting of cancer cell metabolism. Journal of Molecular Medicine (Berlin), 89(3), 205–212. doi: 10.1007/s00109-011-0730-x. [DOI] [PMC free article] [PubMed]
  20. Hirschey, M. D., et al. (2015). Dysregulated metabolism contributes to oncogenesis. Seminars in Cancer Biology, 35(Suppl), S129–S150. doi: 10.1016/j.semcancer.2015.10.002. [DOI] [PMC free article] [PubMed]
  21. Strickaert, A., et al. (2016). Cancer heterogeneity is not compatible with one unique cancer cell metabolic map. Oncogene, 36, 2637. doi: 10.1038/onc.2016.411. [DOI] [PMC free article] [PubMed]
  22. Nabi, K., & Le, A. (2021). The intratumoral heterogeneity of cancer metabolism. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_11 doi: 10.1007/978-3-030-65768-0_11. [DOI] [PMC free article] [PubMed]
  23. Antonio, M. J., Zhang, C., & Le, A. (2021). Different tumor microenvironments lead to different metabolic phenotypes. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_10 doi: 10.1007/978-3-030-65768-0_10. [DOI] [PMC free article] [PubMed]
  24. Catalina-Rodriguez, O., et al. (2012). The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget, 3(10), 1220–1235. doi: 10.18632/oncotarget.714. [DOI] [PMC free article] [PubMed]
  25. Szutowicz, A., Kwiatkowski, J., & Angielski, S. (1979). Lipogenetic and glycolytic enzyme activities in carcinoma and nonmalignant diseases of the human breast. British Journal of Cancer, 39(6), 681–687. doi: 10.1038/bjc.1979.120. [DOI] [PMC free article] [PubMed]
  26. Migita, T., et al. (2008). ATP citrate lyase: Activation and therapeutic implications in non-small cell lung cancer. Cancer Research, 68(20), 8547. doi: 10.1158/0008-5472.CAN-08-1235. [DOI] [PubMed]
  27. Yahagi, N., et al. (2005). Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma. European Journal of Cancer, 41(9), 1316–1322. doi: 10.1016/j.ejca.2004.12.037. [DOI] [PubMed]
  28. Turyn, J., et al. (2003). Increased activity of glycerol 3-phosphate dehydrogenase and other lipogenic enzymes in human bladder cancer. Hormone and Metabolic Research, 35(10), 565–569. doi: 10.1055/s-2003-43500. [DOI] [PubMed]
  29. McGarry, J. D., Leatherman, G. F., & Foster, D. W. (1978). Carnitine palmitoyltransferase. I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. Journal of Biological Chemistry, 253(12), 4128–4136. [PubMed]
  30. Wang, C., et al. (2015). The acetyl-CoA carboxylase enzyme: A target for cancer therapy? Expert Review of Anticancer Therapy, 15(6), 667–676. doi: 10.1586/14737140.2015.1038246. [DOI] [PubMed]
  31. Savage, D. B., et al. (2006). Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. Journal of Clinical Investigation, 116(3), 817–824. doi: 10.1172/JCI27300. [DOI] [PMC free article] [PubMed]
  32. Milgraum, L. Z., et al. (1997). Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. Clinical Cancer Research, 3(11), 2115–2120. [PubMed]
  33. Swinnen, J. V., et al. (2000). Selective activation of the fatty acid synthesis pathway in human prostate cancer. International Journal of Cancer, 88(2), 176–179. doi: 10.1002/1097-0215(20001015)88:2<176::aid-ijc5>3.0.co;2-3. [DOI] [PubMed]
  34. Nelson, M. E., et al. (2017). Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defense and promoting cell survival. Nature Communications, 8, 14689. doi: 10.1038/ncomms14689. [DOI] [PMC free article] [PubMed]
  35. The Cancer Genome Atlas Research Network. (2013). Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature, 499(7456), 43–49. doi: 10.1038/nature12222. [DOI] [PMC free article] [PubMed]
  36. Calvisi, D. F., et al. (2011). Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling promotes development of human hepatocellular carcinoma. Gastroenterology, 140(3), 1071–1083.e5. doi: 10.1053/j.gastro.2010.12.006. [DOI] [PMC free article] [PubMed]
  37. Hilvo, M., et al. (2011). Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast Cancer progression. Cancer Research, 71(9), 3236–3245. doi: 10.1158/0008-5472.CAN-10-3894. [DOI] [PubMed]
  38. Beckers, A., et al. (2007). Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Research, 67(17), 8180–8187. doi: 10.1158/0008-5472.CAN-07-0389. [DOI] [PubMed]
  39. Jones, J. E. C., et al. (2017). Inhibition of acetyl-CoA carboxylase 1 (ACC1) and 2 (ACC2) reduces proliferation and De novo lipogenesis of EGFRvIII human glioblastoma cells. PLoS One, 12(1), e0169566. doi: 10.1371/journal.pone.0169566. [DOI] [PMC free article] [PubMed]
  40. Petrova, E., et al. (2017). Acetyl-CoA carboxylase inhibitors attenuate WNT and hedgehog signaling and suppress pancreatic tumor growth. Oncotarget, 8(30), 48660–48670. doi: 10.18632/oncotarget.12650. [DOI] [PMC free article] [PubMed]
  41. Rios Garcia, M., et al. (2017). Acetyl-CoA carboxylase 1-dependent protein acetylation controls breast cancer metastasis and recurrence. Cell Metabolism, 26(6), 842–855.e5. doi: 10.1016/j.cmet.2017.09.018. [DOI] [PubMed]
  42. Zakikhani, M., et al. (2006). Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Research, 66(21), 10269–10273. doi: 10.1158/0008-5472.CAN-06-1500. [DOI] [PubMed]
  43. Knowles, L. M., et al. (2008). Inhibition of fatty-acid synthase induces caspase-8-mediated tumor cell apoptosis by up-regulating DDIT4. Journal of Biological Chemistry, 283(46), 31378–31384. doi: 10.1074/jbc.M803384200. [DOI] [PMC free article] [PubMed]
  44. Moreau, K., et al. (2006). BRCA1 affects lipid synthesis through its interaction with acetyl- CoA carboxylase. Journal of Biological Chemistry, 281(6), 3172–3181. doi: 10.1074/jbc.M504652200. [DOI] [PubMed]
  45. Chajès, V., et al. (2006). Acetyl-CoA carboxylase α is essential to breast cancer cell survival. Cancer Research, 66(10), 5287–5294. doi: 10.1158/0008-5472.CAN-05-1489. [DOI] [PubMed]
  46. Swinnen, J. V., Brusselmans, K., & Verhoeven, G. (2006). Increased lipogenesis in cancer cells: New players, novel targets. Current Opinion in Clinical Nutrition and Metabolic Care, 9(4), 358–365. doi: 10.1097/01.mco.0000232894.28674.30. [DOI] [PubMed]
  47. Alo, P. L., et al. (1996). Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer, 77(3), 474–482. doi: 10.1002/(SICI)1097-0142(19960201)77:3<474::AID-CNCR8>3.0.CO;2-K. [DOI] [PubMed]
  48. Swinnen, J. V., et al. (2002). Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. International Journal of Cancer, 98(1), 19–22. doi: 10.1002/ijc.10127. [DOI] [PubMed]
  49. Kridel, S. J., et al. (2004). Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Research, 64(6), 2070–2075. doi: 10.1158/0008-5472.can-03-3645. [DOI] [PubMed]
  50. Zaytseva, Y. Y., et al. (2012). Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Research, 72(6), 1504–1517. doi: 10.1158/0008-5472.CAN-11-4057. [DOI] [PMC free article] [PubMed]
  51. Heuer, T. S., et al. (2017). FASN inhibition and Taxane treatment combine to enhance anti-tumor efficacy in diverse Xenograft tumor models through disruption of tubulin palmitoylation and microtubule organization and FASN inhibition-mediated effects on oncogenic signaling and gene expression. eBioMedicine, 16, 51–62. doi: 10.1016/j.ebiom.2016.12.012. [DOI] [PMC free article] [PubMed]
  52. Jiang, L., et al. (2015). Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition. Oncogene, 34(30), 3908–3916. doi: 10.1038/onc.2014.321. [DOI] [PMC free article] [PubMed]
  53. Dean, E. J., et al. (2016). Preliminary activity in the first in human study of the first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640. Journal of Clinical Oncology, 34(15_ suppl), 2512–2512.
  54. Falkenburger, B. H., et al. (2010). Phosphoinositides: Lipid regulators of membrane proteins. The Journal of Physiology, 588(Pt 17), 3179–3185. doi: 10.1113/jphysiol.2010.192153. [DOI] [PMC free article] [PubMed]
  55. Samuels, Y., et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science, 304(5670), 554. doi: 10.1126/science.1096502. [DOI] [PubMed]
  56. Samuels, Y., & Velculescu, V. E. (2004). Oncogenic mutations of PIK3CA in human cancers. Cell Cycle, 3(10), 1221–1224. doi: 10.4161/cc.3.10.1164. [DOI] [PubMed]
  57. Tennant, D. A., Duran, R. V., & Gottlieb, E. (2010). Targeting metabolic transformation for cancer therapy. Nature Reviews Cancer, 10(4), 267–277. doi: 10.1038/nrc2817. [DOI] [PubMed]
  58. Ricoult, S. J. H., et al. (2016). Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene, 35(10), 1250–1260. doi: 10.1038/onc.2015.179. [DOI] [PMC free article] [PubMed]
  59. Gouw, A. M., et al. (2017). Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 114(17), 4300–4305. doi: 10.1073/pnas.1617709114. [DOI] [PMC free article] [PubMed]
  60. Polivka, J., & Janku, F. (2014). Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacology & Therapeutics, 142(2), 164–175. doi: 10.1016/j.pharmthera.2013.12.004. [DOI] [PubMed]
  61. Downward, J. (2003). Targeting RAS signaling pathways in cancer therapy. Nature Reviews Cancer, 3, 11. doi: 10.1038/nrc969. [DOI] [PubMed]
  62. Yang, Y.-A., et al. (2002). Activation of fatty acid synthesis during neoplastic transformation: Role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Experimental Cell Research, 279(1), 80–90. doi: 10.1006/excr.2002.5600. [DOI] [PubMed]
  63. Che, L., et al. (2017). Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma. Cell Cycle, 16(6), 499–507. doi: 10.1080/15384101.2017.1282586. [DOI] [PMC free article] [PubMed]
  64. Ventura, R., et al. (2015). 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(8), 808–824. doi: 10.1016/j.ebiom.2015.06.020. [DOI] [PMC free article] [PubMed]
  65. Hatzivassiliou, G., et al. (2005). ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell, 8(4), 311–321. doi: 10.1016/j.ccr.2005.09.008. [DOI] [PubMed]
  66. Hanai, J.-I., et al. (2012). Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. Journal of Cellular Physiology, 227(4), 1709–1720. doi: 10.1002/jcp.22895. [DOI] [PMC free article] [PubMed]
  67. Svensson, R. U., et al. (2016). Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small cell lung cancer in preclinical models. Nature Medicine, 22(10), 1108–1119. doi: 10.1038/nm.4181. [DOI] [PMC free article] [PubMed]
  68. Uddin, S., et al. (2010). Inhibition of fatty acid synthase suppresses c-Met receptor kinase and induces apoptosis in diffuse large B-cell lymphoma. Molecular Cancer Therapeutics, 9(5), 1244–1255. doi: 10.1158/1535-7163.MCT-09-1061. [DOI] [PubMed]
  69. Wieduwilt, M. J., & Moasser, M. M. (2008). The epidermal growth factor receptor family: Biology driving targeted therapeutics. Cellular and Molecular Life Sciences: CMLS, 65(10), 1566–1584. doi: 10.1007/s00018-008-7440-8. [DOI] [PMC free article] [PubMed]
  70. Sierra, J. R., & Tsao, M.-S. (2011). c-MET as a potential therapeutic target and biomarker in cancer. Therapeutic Advances in Medical Oncology, 3(1 Suppl), S21–S35. doi: 10.1177/1758834011422557. [DOI] [PMC free article] [PubMed]
  71. Hanai, J. I., et al. (2013). ATP citrate lyase knockdown impacts cancer stem cells in vitro. Cell Death & Disease, 4(6), e696. doi: 10.1038/cddis.2013.215. [DOI] [PMC free article] [PubMed]
  72. Chen, Y., et al. (2016). mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer. Oncotarget, 7(18), 25224–25240. doi: 10.18632/oncotarget.8279. [DOI] [PMC free article] [PubMed]
  73. Corominas-Faja, B., et al. (2014). Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells. Oncotarget, 5(18), 8306–8316. doi: 10.18632/oncotarget.2059. [DOI] [PMC free article] [PubMed]
  74. Menendez, J. A., et al. (2004). Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 101(29), 10715–10720. doi: 10.1073/pnas.0403390101. [DOI] [PMC free article] [PubMed]
  75. Giró-Perafita, A., et al. (2016). Preclinical evaluation of fatty acid synthase and EGFR inhibition in triple-negative breast cancer. Clinical Cancer Research, 22(18), 4687–4697. doi: 10.1158/1078-0432.CCR-15-3133. [DOI] [PubMed]
  76. Menendez, J. A., & Lupu, R. (2017). Fatty acid synthase regulates estrogen receptor-α signaling in breast cancer cells. Oncogene, 6, e299. doi: 10.1038/oncsis.2017.4. [DOI] [PMC free article] [PubMed]
  77. Vellaichamy, A., et al. (2010). “Topological significance” analysis of gene expression and proteomic profiles from prostate cancer cells reveals key mechanisms of androgen response. PLoS One, 5(6), e10936. doi: 10.1371/journal.pone.0010936. [DOI] [PMC free article] [PubMed]
  78. Li, J.-N., et al. (2001). Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Research, 61(4), 1493–1499. [PubMed]
  79. Liu, D., et al. (2016). Wnt/β-catenin signaling participates in the regulation of lipogenesis in the liver of juvenile turbot (Scophthalmus maximus L.). Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 191, 155–162. doi: 10.1016/j.cbpb.2015.11.002. [DOI] [PubMed]
  80. Seo, M. H., et al. (2016). Exendin-4 inhibits hepatic lipogenesis by increasing β-catenin signaling. PLoS One, 11(12), e0166913. doi: 10.1371/journal.pone.0166913. [DOI] [PMC free article] [PubMed]
  81. Gelebart, P., et al. (2012). Blockade of fatty acid synthase triggers significant apoptosis in mantle cell lymphoma. PLoS One, 7(4), e33738. doi: 10.1371/journal.pone.0033738. [DOI] [PMC free article] [PubMed]
  82. Yoon, S., et al. (2007). Up-regulation of acetyl-CoA carboxylase α and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. Journal of Biological Chemistry, 282(36), 26122–26131. doi: 10.1074/jbc.M702854200. [DOI] [PubMed]
  83. Daemen, A., et al. (2015). Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 112(32), E4410–E4417. doi: 10.1073/pnas.1501605112. [DOI] [PMC free article] [PubMed]
  84. Xie, H., & Simon, M. C. (2017). Oxygen availability and metabolic reprogramming in cancer. The Journal of Biological Chemistry, 292(41), 16825–16832. doi: 10.1074/jbc.R117.799973. [DOI] [PMC free article] [PubMed]
  85. Bensaad, K., et al. (2014). Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation. Cell Reports, 9(1), 349–365. doi: 10.1016/j.celrep.2014.08.056. [DOI] [PubMed]
  86. Kamphorst, J. J., et al. (2013). Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proceedings of the National Academy of Sciences of the United States of America, 110(22), 8882–8887. doi: 10.1073/pnas.1307237110. [DOI] [PMC free article] [PubMed]
  87. Young, R. M., et al. (2013). Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes & Development, 27(10), 1115–1131. doi: 10.1101/gad.198630.112. [DOI] [PMC free article] [PubMed]
  88. Sounni, N. E., et al. (2014). Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metabolism, 20(2), 280–294. doi: 10.1016/j.cmet.2014.05.022. [DOI] [PubMed]
  89. Daniëls, V. W., et al. (2014). Cancer cells differentially activate and thrive on de novo lipid synthesis pathways in a low-lipid environment. PLoS One, 9(9), e106913. doi: 10.1371/journal.pone.0106913. [DOI] [PMC free article] [PubMed]
  90. Zaidi, N., et al. (2012). ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms. Molecular Cancer Therapeutics, 11(9), 1925–1935. doi: 10.1158/1535-7163.MCT-12-0095. [DOI] [PubMed]
  91. Lakhter, A. J., et al. (2016). Glucose-independent acetate metabolism promotes melanoma cell survival and tumor growth. The Journal of Biological Chemistry, 291(42), 21869–21879. doi: 10.1074/jbc.M115.712166. [DOI] [PMC free article] [PubMed]
  92. Tamura, K., et al. (2009). Novel lipogenic enzyme ELOVL7 is involved in prostate cancer growth through saturated long-chain fatty acid metabolism. Cancer Research, 69(20), 8133–8140. doi: 10.1158/0008-5472.CAN-09-0775. [DOI] [PubMed]
  93. Jump, D. B., Torres-Gonzalez, M., & Olson, L. K. (2011). Soraphen A, an inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation. Biochemical Pharmacology, 81(5), 649–660. doi: 10.1016/j.bcp.2010.12.014. [DOI] [PMC free article] [PubMed]
  94. Yang, W. S., et al. (2012). Proteomic approach reveals FKBP4 and S100A9 as potential prediction markers of therapeutic response to neoadjuvant chemotherapy in patients with breast cancer. Journal of Proteome Research, 11(2), 1078–1088. doi: 10.1021/pr2008187. [DOI] [PubMed]
  95. Clendening, J. W., et al. (2010). Dysregulation of the mevalonate pathway promotes transformation. Proceedings of the National Academy of Sciences, 107(34), 15051–15056. doi: 10.1073/pnas.0910258107. [DOI] [PMC free article] [PubMed]
  96. Platz, E. A., et al. (2006). Statin drugs and risk of advanced prostate Cancer. Journal of the National Cancer Institute, 98(24), 1819–1825. doi: 10.1093/jnci/djj499. [DOI] [PubMed]
  97. Poynter, J. N., et al. (2005). Statins and the risk of colorectal cancer. New England Journal of Medicine, 352(21), 2184–2192. doi: 10.1056/NEJMoa043792. [DOI] [PubMed]
  98. Nielsen, S. F., Nordestgaard, B. G., & Bojesen Statin, S. E. (2012). Use and reduced cancer-related mortality. New England Journal of Medicine, 367(19), 1792–1802. doi: 10.1056/NEJMoa1201735. [DOI] [PubMed]
  99. Clendening, J. W., & Penn, L. Z. (2012). Targeting tumor cell metabolism with statins. Oncogene, 31, 4967. doi: 10.1038/onc.2012.6. [DOI] [PubMed]
  100. Campbell, M. J., et al. (2006). Breast cancer growth prevention by statins. Cancer Research, 66(17), 8707–8714. doi: 10.1158/0008-5472.CAN-05-4061. [DOI] [PubMed]
  101. Zhong, C., et al. (2014). HMGCR is necessary for the tumorigenicity of esophageal squamous cell carcinoma and is regulated by Myc. Tumor Biology, 35(5), 4123–4129. doi: 10.1007/s13277-013-1539-8. [DOI] [PubMed]
  102. Wang, X., et al. (2017). MYC-regulated mevalonate metabolism maintains brain tumor-initiating cells. Cancer Research, 77(18), 4947–4960. doi: 10.1158/0008-5472.CAN-17-0114. [DOI] [PMC free article] [PubMed]
  103. Juneja, M., et al. (2017). Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1. PLoS Biology, 15(6), e2000784. doi: 10.1371/journal.pbio.2000784. [DOI] [PMC free article] [PubMed]
  104. Fujiwara, D., et al. (2017). Statins induce apoptosis through inhibition of Ras signaling pathways and enhancement of Bim and p27 expression in human hematopoietic tumor cells. Tumor Biology, 39(10), 1010428317734947. doi: 10.1177/1010428317734947. [DOI] [PubMed]
  105. Karagkounis, G., et al. (2017). Simvastatin enhances radiation sensitivity of colorectal cancer cells. Surgical Endoscopy, 32(3), 1533–1539. doi: 10.1007/s00464-017-5841-1. [DOI] [PubMed]
  106. Lipkin, S. M., et al. (2010). Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. Cancer Prevention Research, 3(5), 597–603. doi: 10.1158/1940-6207.CAPR-10-0007. [DOI] [PubMed]
  107. Menter, D. G., et al. (2011). Differential effects of pravastatin and simvastatin on the growth of tumor cells from different organ sites. PLoS One, 6(12), e28813. doi: 10.1371/journal.pone.0028813. [DOI] [PMC free article] [PubMed]
  108. Lee, Y., et al. (2017). Randomized phase II study of afatinib plus simvastatin versus afatinib alone in previously treated patients with advanced nonadenocarcinomatous non-small cell lung cancer. Cancer Research and Treatment: Official Journal of Korean Cancer Association, 49(4), 1001–1011. doi: 10.4143/crt.2016.546. [DOI] [PMC free article] [PubMed]
  109. Baas, J. M., et al. (2015). Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients. Anti-Cancer Drugs, 26(8), 872–877. doi: 10.1097/CAD.0000000000000255. [DOI] [PubMed]
  110. Baas, J. M., et al. (2015). Safety and efficacy of the addition of simvastatin to cetuximab in previously treated KRAS mutant metastatic colorectal cancer patients. Investigational New Drugs, 33(6), 1242–1247. doi: 10.1007/s10637-015-0285-8. [DOI] [PMC free article] [PubMed]
  111. Zaidi, N., et al. (2013). Lipogenesis and lipolysis: The pathways exploited by the cancer cells to acquire fatty acids. Progress in Lipid Research, 52(4), 585–589. doi: 10.1016/j.plipres.2013.08.005. [DOI] [PMC free article] [PubMed]
  112. Pavlova, N. N., & Thompson, C. B. (2016). The emerging hallmarks of cancer metabolism. Cell Metabolism, 23(1), 27–47. doi: 10.1016/j.cmet.2015.12.006. [DOI] [PMC free article] [PubMed]
  113. Kuemmerle, N. B., et al. (2011). Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Molecular Cancer Therapeutics, 10(3), 427–436. doi: 10.1158/1535-7163.MCT-10-0802. [DOI] [PMC free article] [PubMed]
  114. van’t Veer, M. B., et al. (2006). The predictive value of lipoprotein lipase for survival in chronic lymphocytic leukemia. Haematologica, 91(1), 56–63. [PubMed]
  115. Hale, J. S., et al. (2014). Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression. Stem Cells, 32(7), 1746–1758. doi: 10.1002/stem.1716. [DOI] [PMC free article] [PubMed]
  116. Nath, A., et al. (2015). Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Scientific Reports, 5, 14752. doi: 10.1038/srep14752. [DOI] [PMC free article] [PubMed]
  117. Guillaumond, F., et al. (2015). Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 112(8), 2473–2478. doi: 10.1073/pnas.1421601112. [DOI] [PMC free article] [PubMed]
  118. Chaffer, C. L., & Weinberg, R. A. (2011). A perspective on cancer cell metastasis. Science, 331(6024), 1559–1564. doi: 10.1126/science.1203543. [DOI] [PubMed]
  119. Hua, Y., et al. (2011). Dynamic metabolic transformation in tumor invasion and metastasis in mice with LM-8 osteosarcoma cell transplantation. Journal of Proteome Research, 10(8), 3513–3521. doi: 10.1021/pr200147g. [DOI] [PubMed]
  120. Jung, Y. Y., Kim, H. M., & Koo, J. S. (2015). Expression of lipid metabolism-related proteins in metastatic breast cancer. PLoS One, 10(9), e0137204. doi: 10.1371/journal.pone.0137204. [DOI] [PMC free article] [PubMed]
  121. Nath, A., & Chan, C. (2016). Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers. Scientific Reports, 6, 18669. doi: 10.1038/srep18669. [DOI] [PMC free article] [PubMed]
  122. Uray, I. P., Liang, Y., & Hyder, S. M. (2004). Estradiol down-regulates CD36 expression in human breast cancer cells. Cancer Letters, 207(1), 101–107. doi: 10.1016/j.canlet.2003.10.021. [DOI] [PubMed]
  123. Balaban, S., et al. (2015). Obesity and cancer progression: Is there a role of fatty acid metabolism? BioMed Research International, 2015, 274585. doi: 10.1155/2015/274585. [DOI] [PMC free article] [PubMed]
  124. Schoors, S., et al. (2015). Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature, 520(7546), 192–197. doi: 10.1038/nature14362. [DOI] [PMC free article] [PubMed]
  125. McDonnell, E., et al. (2016). Lipids reprogram metabolism to become a major carbon source for histone acetylation. Cell Reports, 17(6), 1463–1472. doi: 10.1016/j.celrep.2016.10.012. [DOI] [PMC free article] [PubMed]
  126. Padanad, M. S., et al. (2016). Fatty acid oxidation mediated by acyl-CoA Synthetase long-chain 3 is required for mutant KRAS lung tumorigenesis. Cell Reports, 16(6), 1614–1628. doi: 10.1016/j.celrep.2016.07.009. [DOI] [PMC free article] [PubMed]
  127. Liu, Y. (2006). Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer and Prostatic Diseases, 9(3), 230–234. doi: 10.1038/sj.pcan.4500879. [DOI] [PubMed]
  128. Camarda, R., et al. (2016). Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nature Medicine, 22(4), 427–432. doi: 10.1038/nm.4055. [DOI] [PMC free article] [PubMed]
  129. Comerford, S. A., et al. (2014). Acetate dependence of tumors. Cell, 159(7), 1591–1602. doi: 10.1016/j.cell.2014.11.020. [DOI] [PMC free article] [PubMed]
  130. Mashimo, T., et al. (2014). Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell, 159(7), 1603–1614. doi: 10.1016/j.cell.2014.11.025. [DOI] [PMC free article] [PubMed]
  131. Qu, Q., et al. (2016). Fatty acid oxidation and carnitine palmitoyltransferase I: Emerging therapeutic targets in cancer. Cell Death & Disease, 7(5), e2226. doi: 10.1038/cddis.2016.132. [DOI] [PMC free article] [PubMed]
  132. Carrasco, P., et al. (2013). Carnitine palmitoyltransferase 1C deficiency causes motor impairment and hypoactivity. Behavioural Brain Research, 256, 291–297. doi: 10.1016/j.bbr.2013.08.004. [DOI] [PubMed]
  133. Zaugg, K., et al. (2011). Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes & Development, 25(10), 1041–1051. doi: 10.1101/gad.1987211. [DOI] [PMC free article] [PubMed]
  134. Wakil, S. J., & Abu-Elheiga, L. A. (2009). Fatty acid metabolism: Target for metabolic syndrome. Journal of Lipid Research, 50(Suppl), S138–S143. doi: 10.1194/jlr.R800079-JLR200. [DOI] [PMC free article] [PubMed]
  135. Du, W., et al. (2017). HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nature Communications, 8, 1769. doi: 10.1038/s41467-017-01965-8. [DOI] [PMC free article] [PubMed]
  136. Huang, D., et al. (2014). HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Reports, 8(6), 1930–1942. doi: 10.1016/j.celrep.2014.08.028. [DOI] [PubMed]
  137. Fragasso, G., et al. (2009). Effects of metabolic approach in diabetic patients with coronary artery disease. Current Pharmaceutical Design, 15(8), 857–862. doi: 10.2174/138161209787582093. [DOI] [PubMed]
  138. Holubarsch, C. J., et al. (2007). A double-blind, randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: The ERGO (etomoxir for the recovery of glucose oxidation) study. Clinical Science, 113(4), 205–212. doi: 10.1042/CS20060307. [DOI] [PubMed]
  139. Lodhi, I. J., & Semenkovich, C. F. (2014). Peroxisomes: A nexus for lipid metabolism and cellular signaling. Cell Metabolism, 19(3), 380–392. doi: 10.1016/j.cmet.2014.01.002. [DOI] [PMC free article] [PubMed]
  140. Valença, I., et al. (2015). Localization of MCT2 at peroxisomes is associated with malignant transformation in prostate cancer. Journal of Cellular and Molecular Medicine, 19(4), 723–733. doi: 10.1111/jcmm.12481. [DOI] [PMC free article] [PubMed]
  141. Wang, Y.-X. (2010). PPARs: Diverse regulators in energy metabolism and metabolic diseases. Cell Research, 20(2), 124–137. doi: 10.1038/cr.2010.13. [DOI] [PMC free article] [PubMed]
  142. Bensinger, S. J., & Tontonoz, P. (2008). Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature, 454, 470. doi: 10.1038/nature07202. [DOI] [PubMed]
  143. Peters, J. M., Shah, Y. M., & Gonzalez, F. J. (2012). The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nature Reviews Cancer, 12(3), 181–195. doi: 10.1038/nrc3214. [DOI] [PMC free article] [PubMed]
  144. Yousefi, B., et al. (2016). Peroxisome proliferator-activated receptors and their ligands in cancer drug resistance: Opportunity or challenge. Anti-Cancer Agents in Medicinal Chemistry, 16(12), 1541–1548. doi: 10.2174/1871520616666160204112941. [DOI] [PubMed]
  145. Holden, P. R., & Tugwood, J. D. (1999). Peroxisome proliferator-activated receptor alpha: Role in rodent liver cancer and species differences. Journal of Molecular Endocrinology, 22(1), 1–8. doi: 10.1677/jme.0.0220001. [DOI] [PubMed]
  146. Wang, X., et al. (2016). PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions. Oncogene, 5(6), e232. doi: 10.1038/oncsis.2016.41. [DOI] [PMC free article] [PubMed]
  147. Vidal-Puig, A. J., et al. (1997). Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. Journal of Clinical Investigation, 99(10), 2416–2422. doi: 10.1172/JCI119424. [DOI] [PMC free article] [PubMed]
  148. Robbins, G. T., & Nie, D. (2012). PPAR gamma, bioactive lipids, and cancer progression. Frontiers in Bioscience: A Journal and Virtual Library, 17, 1816–1834. doi: 10.2741/4021. [DOI] [PMC free article] [PubMed]
  149. Corbet, C., & Feron, O. (2017). Cancer cell metabolism and mitochondria: Nutrient plasticity for TCA cycle fueling. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1868(1), 7–15. doi: 10.1016/j.bbcan.2017.01.002. [DOI] [PubMed]
  150. Elgogary, A., et al. (2016). Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(36), E5328–E5336. doi: 10.1073/pnas.1611406113. [DOI] [PMC free article] [PubMed]
  151. Bayat Mokhtari, R., et al. (2017). Combination therapy in combating cancer. Oncotarget, 8(23), 38022–38043. doi: 10.18632/oncotarget.16723. [DOI] [PMC free article] [PubMed]
  152. Zhao, B., Hemann, M. T., & Lauffenburger, D. A. (2014). Intratumor heterogeneity alters most effective drugs in designed combinations. Proceedings of the National Academy of Sciences of the United States of America, 111(29), 10773–10778. doi: 10.1073/pnas.1323934111. [DOI] [PMC free article] [PubMed]
  153. Benfeitas, R., et al. (2017). New challenges to study heterogeneity in cancer redox metabolism. Frontiers in Cell and Development Biology, 5, 65. doi: 10.3389/fcell.2017.00065. [DOI] [PMC free article] [PubMed]
  154. Agren, R., et al. (2012). Reconstruction of genome-scale active metabolic networks for 69 human cell types and 16 cancer types using INIT. PLoS Computational Biology, 8(5), e1002518. doi: 10.1371/journal.pcbi.1002518. [DOI] [PMC free article] [PubMed]

RESOURCES