Advertisement

The Heterogeneity of Lipid Metabolism in Cancer

  • Joshua K. Park
  • Nathan J. Coffey
  • Aaron Limoges
  • Anne Le
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1063)

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 for cancer therapy is still an open question.

Keywords

Cancer metabolism Tumor heterogeneity Lipid synthesis Fatty acid oxidation Fatty acid uptake Metastasis Lipidomics 

Abbreviations

4-HNE

4-Hydroxy-nonenal

ω-3/6

Omega-3/6 fatty acid

ACC

Acetyl-coenzyme A carboxylase

ACLY

Adenosine triphosphate citrate lyase

ACSL3

Acyl-coenzyme A synthetase long-chain family member 3

ACSS2

Acyl-coenzyme A synthetase short-chain family member 2

AMPK

Adenosine monophosphate-activated protein kinase

ATP

Adenosine triphosphate

BMI

Body mass index

BTA

Benzene-tricarboxylate

CD36

Cluster of differentiation 36 protein

CTP

Citrate transporter protein

CoA

Coenzyme A

CPT1

Carnitine palmitoyltransferase 1

DNA

Deoxyribonucleic acid

DNLS

De novo lipid synthesis

EMT

Epithelial-mesenchymal transition

ERS

Endoplasmic reticulum stress

FADH2

Flavin adenine dinucleotide

FAO

Fatty acid oxidation

FAS

Fatty acid synthase

FATP

Fatty acid transport protein

GBM

Glioblastoma multiforme

HFD

High-fat diet

HMGCR

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

IDH

Isocitrate dehydrogenase

LD

Lipid droplet

LDL

Low-density lipoprotein

LPL

Lipoprotein lipase

NADH

Nicotinamide adenine dinucleotide

NADPH

Nicotinamide adenine dinucleotide phosphate

PE

Phosphatidylethanolamine

PIP2

Phosphatidylinositol-4,5-bisphosphate

PUFA

Polyunsaturated fatty acid

ROS

Reactive oxygen species

SCD

Stearoyl-coenzyme A desaturase

TCA

Tricarboxylic acid

TG

Triglyceride

TME

Tumor microenvironment

Notes

Acknowledgments

We thank Dr. Resat Cinar, PhD, MBA, for his support and Mr. Daniel C. McCaskey, JD, for his review of the manuscript.

References

  1. 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.CrossRefGoogle Scholar
  2. 2.
    Shevchenko, A., & Simons, K. (2010). Lipidomics: Coming to grips with lipid diversity. Nature Reviews Molecular Cell Biology, 11, 593.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Yang, K., & Han, X. (2016). Lipidomics: Techniques, applications, and outcomes related to biomedical sciences. Trends in Biochemical Sciences, 41(11), 954–969.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    DeBerardinis, R. J., & Chandel, N. S. (2016). Fundamentals of cancer metabolism. Science Advances, 2(5), e1600200.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Beloribi-Djefaflia, S., Vasseur, S., & Guillaumond, F. (2016). Lipid metabolic reprogramming in cancer cells. Oncogene, 5, e189.CrossRefGoogle Scholar
  6. 6.
    Zalba, S., & ten Hagen, T. L. M. (2017). Cell membrane modulation as adjuvant in cancer therapy. Cancer Treatment Reviews, 52, 48–57.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 10.
    Keckesova, Z., et al. (2017). LACTB is a tumour suppressor that modulates lipid metabolism and cell state. Nature, 543, 681.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Wang, D., & Dubois, R. N. (2010). Eicosanoids and cancer. Nature Reviews. Cancer, 10(3), 181–193.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Pascual, G., et al. (2016). Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature, 541, 41.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Viswanathan, V. S., et al. (2017). Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature, 547, 453.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Luo, X., et al. (2017). Emerging roles of lipid metabolism in cancer metastasis. Molecular Cancer, 16, 76.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 18.
    Greaves, M. (2015). Evolutionary determinants of cancer. Cancer Discovery, 5(8), 806–820.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Jamal-Hanjani, M., et al. (2015). Translational implications of tumor heterogeneity. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 21(6), 1258–1266.CrossRefGoogle Scholar
  20. 20.
    McGranahan, N., & Swanton, C. (2017). Clonal heterogeneity and tumor evolution: Past, present, and the future. Cell, 168(4), 613–628.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Strickaert, A., et al. (2016). Cancer heterogeneity is not compatible with one unique cancer cell metabolic map. Oncogene, 36, 2637.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Marusyk, A., Almendro, V., & Polyak, K. (2012). Intra-tumour heterogeneity: A looking glass for cancer? Nature Reviews Cancer, 12, 323.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Hiley, C., et al. (2014). Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine. Genome Biology, 15(8), 453.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Catalina-Rodriguez, O., et al. (2012). The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget, 3(10), 1220–1235.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Migita, T., et al. (2008). ATP citrate lyase: Activation and therapeutic implications in non–small cell lung cancer. Cancer Research, 68(20), 8547.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Yahagi, N., et al. (2005). Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma. European Journal of Cancer, 41(9), 1316–1322.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 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.PubMedPubMedCentralGoogle Scholar
  30. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 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.PubMedPubMedCentralGoogle Scholar
  33. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Nelson, M. E., et al. (2017). Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival. Nature Communications, 8, 14689.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    The Cancer Genome Atlas Research Network. (2013). Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature, 499(7456), 43–49.CrossRefPubMedCentralGoogle Scholar
  36. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 42.
    Zakikhani, M., et al. (2006). Metformin is an AMP kinase–dependent growth inhibitor for breast Cancer cells. Cancer Research, 66(21), 10269–10273.CrossRefPubMedGoogle Scholar
  43. 43.
    Knowles, L.M., et al. (2008). Inhibition of Fatty-acid Synthase Induces Caspase-8-mediated Tumor Cell Apoptosis by Up-regulating DDIT4. The Journal of Biological Chemistry, 283(46), 31378–31384.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefPubMedGoogle Scholar
  45. 45.
    Chajès, V., et al. (2006). Acetyl-CoA carboxylase α is essential to breast cancer cell survival. Cancer Research, 66(10), 5287–5294.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.CrossRefPubMedGoogle Scholar
  48. 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.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefPubMedGoogle Scholar
  50. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 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.CrossRefPubMedGoogle Scholar
  52. 52.
    Jiang, L., et al. (2015). Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition. Oncogene, 34(30), 3908–3916.CrossRefPubMedGoogle Scholar
  53. 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.CrossRefGoogle Scholar
  54. 54.
    Falkenburger, B. H., et al. (2010). Phosphoinositides: Lipid regulators of membrane proteins. The Journal of Physiology, 588(Pt 17), 3179–3185.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Samuels, Y., et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science, 304(5670), 554.CrossRefPubMedGoogle Scholar
  56. 56.
    Samuels, Y., & Velculescu, V. E. (2004). Oncogenic mutations of PIK3CA in human cancers. Cell Cycle, 3(10), 1221–1224.CrossRefPubMedGoogle Scholar
  57. 57.
    Tennant, D. A., Duran, R. V., & Gottlieb, E. (2010). Targeting metabolic transformation for cancer therapy. Nature Reviews. Cancer, 10(4), 267–277.CrossRefPubMedGoogle Scholar
  58. 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.CrossRefPubMedGoogle Scholar
  59. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Polivka, J., & Janku, F. (2014). Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacology & Therapeutics, 142(2), 164–175.CrossRefGoogle Scholar
  61. 61.
    Downward, J. (2003). Targeting RAS signaling pathways in cancer therapy. Nature Reviews Cancer, 3, 11.CrossRefPubMedGoogle Scholar
  62. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Che, L., et al. (2017). Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma. Cell Cycle, 16(6), 499–507.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Hatzivassiliou, G., et al. (2005). ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell, 8(4), 311–321.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Hanai, J. I., et al. (2013). ATP citrate lyase knockdown impacts cancer stem cells in vitro. Cell Death & Disease, 4(6), e696.CrossRefGoogle Scholar
  72. 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.PubMedPubMedCentralGoogle Scholar
  73. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Menendez, J. A., & Lupu, R. (2017). Fatty acid synthase regulates estrogen receptor-α signaling in breast cancer cells. Oncogene, 6, e299.CrossRefGoogle Scholar
  77. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 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.PubMedPubMedCentralGoogle Scholar
  79. 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.CrossRefGoogle Scholar
  80. 80.
    Seo, M. H., et al. (2016). Exendin-4 inhibits hepatic lipogenesis by increasing β-catenin signaling. PLoS One, 11(12), e0166913.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Gelebart, P., et al. (2012). Blockade of fatty acid synthase triggers significant apoptosis in mantle cell lymphoma. PLoS One, 7(4), e33738.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Xie, H., & Simon, M. C. (2017). Oxygen availability and metabolic reprogramming in cancer. The Journal of Biological Chemistry, 292(41), 16825–16832.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 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.CrossRefGoogle Scholar
  88. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 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.CrossRefGoogle Scholar
  96. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Poynter, J. N., et al. (2005). Statins and the risk of colorectal cancer. New England Journal of Medicine, 352(21), 2184–2192.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Clendening, J. W., & Penn, L. Z. (2012). Targeting tumor cell metabolism with statins. Oncogene, 31, 4967.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Campbell, M. J., et al. (2006). Breast cancer growth prevention by statins. Cancer Research, 66(17), 8707–8714.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Zhong, C., et al. (2014). HMGCR is necessary for the tumorigenecity of esophageal squamous cell carcinoma and is regulated by Myc. Tumor Biology, 35(5), 4123–4129.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Wang, X., et al. (2017). MYC-regulated mevalonate metabolism maintains brain tumor–initiating cells. Cancer Research, 77(18), 4947–4960.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Karagkounis, G., et al. (2017). Simvastatin enhances radiation sensitivity of colorectal cancer cells. Surgical Endoscopy, 32(3), 1533–1539.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 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.CrossRefGoogle Scholar
  109. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Pavlova, N. N., & Thompson, C. B. (2016). The emerging hallmarks of Cancer metabolism. Cell Metabolism, 23(1), 27–47.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Kuemmerle, N. B., et al. (2011). Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Molecular Cancer Therapeutics, 10(3), 427–436.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 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.Google Scholar
  115. 115.
    Hale, J. S., et al. (2014). Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression. Stem Cells, 32(7), 1746–1758.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Nath, A., et al. (2015). Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Scientific Reports, 5, 14752.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Chaffer, C. L., & Weinberg, R. A. (2011). A perspective on cancer cell metastasis. Science, 331(6024), 1559–1564.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Balaban, S., et al. (2015). Obesity and cancer progression: Is there a role of fatty acid metabolism? BioMed Research International, 2015, 274585.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Schoors, S., et al. (2015). Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature, 520(7546), 192–197.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    McDonnell, E., et al. (2016). Lipids reprogram metabolism to become a major carbon source for histone acetylation. Cell Reports, 17(6), 1463–1472.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Liu, Y. (2006). Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer and Prostatic Diseases, 9(3), 230–234.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Comerford, S. A., et al. (2014). Acetate dependence of tumors. Cell, 159(7), 1591–1602.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Mashimo, T., et al. (2014). Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell, 159(7), 1603–1614.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Qu, Q., et al. (2016). Fatty acid oxidation and carnitine palmitoyltransferase I: Emerging therapeutic targets in cancer. Cell Death & Disease, 7(5), e2226.CrossRefGoogle Scholar
  132. 132.
    Carrasco, P., et al. (2013). Carnitine palmitoyltransferase 1C deficiency causes motor impairment and hypoactivity. Behavioural Brain Research, 256, 291–297.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 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.CrossRefGoogle Scholar
  134. 134.
    Wakil, S. J., & Abu-Elheiga, L. A. (2009). Fatty acid metabolism: Target for metabolic syndrome. Journal of Lipid Research, 50(Suppl), S138–S143.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Du, W., et al. (2017). HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nature Communications, 8, 1769.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 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.CrossRefPubMedGoogle Scholar
  137. 137.
    Fragasso, G., et al. (2009). Effects of metabolic approach in diabetic patients with coronary artery disease. Current Pharmaceutical Design, 15(8), 857–862.CrossRefPubMedGoogle Scholar
  138. 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.CrossRefPubMedGoogle Scholar
  139. 139.
    Lodhi, I. J., & Semenkovich, C. F. (2014). Peroxisomes: A nexus for lipid metabolism and cellular signaling. Cell Metabolism, 19(3), 380–392.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Wang, Y.-X. (2010). PPARs: Diverse regulators in energy metabolism and metabolic diseases. Cell Research, 20(2), 124–137.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Bensinger, S. J., & Tontonoz, P. (2008). Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature, 454, 470.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 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.CrossRefPubMedGoogle Scholar
  145. 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.CrossRefPubMedGoogle Scholar
  146. 146.
    Wang, X., et al. (2016). PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions. Oncogene, 5(6), e232.CrossRefGoogle Scholar
  147. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 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.CrossRefGoogle Scholar
  149. 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.CrossRefGoogle Scholar
  150. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Bayat Mokhtari, R., et al. (2017). Combination therapy in combating cancer. Oncotarget, 8(23), 38022–38043.PubMedPubMedCentralGoogle Scholar
  152. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Benfeitas, R., et al. (2017). New challenges to study heterogeneity in cancer redox metabolism. Frontiers in Cell and Developmental Biology, 5, 65.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 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.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Joshua K. Park
    • 1
    • 2
  • Nathan J. Coffey
    • 2
  • Aaron Limoges
    • 3
  • Anne Le
    • 4
  1. 1.Department of PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.National Institute on Alcohol Abuse and Alcoholism, National Institutes of HealthBethesdaUSA
  3. 3.Department of Biological SciencesColumbia UniversityNew YorkUSA
  4. 4.Department of Pathology and OncologyJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations