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Metabolic regulation of cell growth and proliferation

Nature Reviews Molecular Cell Biology volume 20, pages 436–450 (2019)Cite this article

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Abstract

Cellular metabolism is at the foundation of all biological activities. The catabolic processes that support cellular bioenergetics and survival have been well studied. By contrast, how cells alter their metabolism to support anabolic biomass accumulation is less well understood. During the commitment to cell proliferation, extensive metabolic rewiring must occur in order for cells to acquire sufficient nutrients such as glucose, amino acids, lipids and nucleotides, which are necessary to support cell growth and to deal with the redox challenges that arise from the increased metabolic activity associated with anabolic processes. Defining the mechanisms of this metabolic adaptation for cell growth and proliferation is now a major focus of research. Understanding the principles that guide anabolic metabolism may ultimately enhance ways to treat diseases that involve deregulated cell growth and proliferation, such as cancer.

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Fig. 1: Glucose uptake and utilization.
Fig. 2: Amino acid sensing and acquisition.
Fig. 3: Fatty acid synthesis.
Fig. 4: Synthesis of pyrimidine and purine nucleotides.
Fig. 5: Metabolic interactions with the extracellular environment.
Fig. 6: Maintaining redox homeostasis in proliferating cells.

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References

  1. Galdieri, L., Mehrotra, S., Yu, S. & Vancura, A. Transcriptional regulation in yeast during diauxic shift and stationary phase. OMICS 14, 629–638 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Marijuan, P. C., Navarro, J. & del Moral, R. On prokaryotic intelligence: strategies for sensing the environment. Biosystems 99, 94–103 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Schaller, G. E., Shiu, S. H. & Armitage, J. P. Two-component systems and their co-option for eukaryotic signal transduction. Curr. Biol. 21, R320–R330 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rheinwald, J. G. & Green, H. Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. Nature 265, 421–424 (1977).

    Article  CAS  PubMed  Google Scholar 

  6. Martin, P. Wound healing—aiming for perfect skin regeneration. Science 276, 75–81 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Nissen, N. N. et al. Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am. J. Pathol. 152, 1445–1452 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Esensten, J. H., Helou, Y. A., Chopra, G., Weiss, A. & Bluestone, J. A. CD28 costimulation: from mechanism to therapy. Immunity 44, 973–988 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Barthel, A. et al. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J. Biol. Chem. 274, 20281–20286 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Rathmell, J. C. et al. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol. Cell. Biol. 23, 7315–7328 (2003). This work demonstrates that growth factor signalling is necessary for mammalian cells to maintain glucose uptake in support of bioenergetics and cell survival.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wieman, H. L., Wofford, J. A. & Rathmell, J. C. Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol. Biol. Cell 18, 1437–1446 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rathmell, J. C., Vander Heiden, M. G., Harris, M. H., Frauwirth, K. A. & Thompson, C. B. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol. Cell 6, 683–692 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Fox, C. J., Hammerman, P. S. & Thompson, C. B. Fuel feeds function: energy metabolism and the T cell response. Nat. Rev. Immunol. 5, 844–852 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Recondo, G., Facchinetti, F., Olaussen, K. A., Besse, B. & Friboulet, L. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat. Rev. Clin. Oncol. 15, 694–708 (2018).

    Article  CAS  PubMed  Google Scholar 

  20. Arteaga, C. L. et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat. Rev. Clin. Oncol. 9, 16–32 (2011).

    Article  PubMed  CAS  Google Scholar 

  21. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7, 606–619 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Almuhaideb, A., Papathanasiou, N. & Bomanji, J. 18F-FDG PET/CT imaging in oncology. Ann. Saudi Med. 31, 3–13 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  Google Scholar 

  27. Faubert, B. et al. Lactate metabolism in human lung tumors. Cell 171, 358–371 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017). Faubert et al. (2017) and Hui et al. (2017) provide the first evidence that lactate in the circulation can act as the major carbon source to fuel the TCA cycle in vivo.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Palm, W. & Thompson, C. B. Nutrient acquisition strategies of mammalian cells. Nature 546, 234–242 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Menon, S. et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771–785 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702–713 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Edinger, A. L. & Thompson, C. B. Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol. Biol. Cell 13, 2276–2288 (2002). This study shows that AKT promotes cell survival and growth in part by maintaining nutrient transporter levels on the plasma membrane.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hannan, K. M. et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol. Cell. Biol. 23, 8862–8877 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wolfson, R. L. & Sabatini, D. M. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 26, 301–309 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Saxton, R. A. et al. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science 351, 53–58 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Wolfson, R. L. et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43–48 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Chantranupong, L. et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165, 153–164 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lu, P. D., Harding, H. P. & Ron, D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J. Cell Biol. 167, 27–33 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Sato, H. et al. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Biochem. Biophys. Res. Commun. 325, 109–116 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Lewerenz, J. & Maher, P. Basal levels of eIF2alpha phosphorylation determine cellular antioxidant status by regulating ATF4 and xCT expression. J. Biol. Chem. 284, 1106–1115 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lopez, A. B. et al. A feedback transcriptional mechanism controls the level of the arginine/lysine transporter cat-1 during amino acid starvation. Biochem. J. 402, 163–173 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang, N. et al. Increased amino acid uptake supports autophagy-deficient cell survival upon glutamine deprivation. Cell Rep. 23, 3006–3020 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Shan, J. et al. The C/ebp-Atf response element (CARE) location reveals two distinct Atf4-dependent, elongation-mediated mechanisms for transcriptional induction of aminoacyl-tRNA synthetase genes in response to amino acid limitation. Nucleic Acids Res. 44, 9719–9732 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ye, J. et al. GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev. 29, 2331–2336 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Siu, F., Bain, P. J., LeBlanc-Chaffin, R., Chen, H. & Kilberg, M. S. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. J. Biol. Chem. 277, 24120–24127 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 43, 869–874 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011). Locasale et al. (2011) and Possemato et al. (2011) provide early evidence that the serine synthesis pathway is upregulated in cancer and that it is critical in mediating tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pacold, M. E. et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat. Chem. Biol. 12, 452–458 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mullarky, E. et al. Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proc. Natl Acad. Sci. USA 113, 1778–1783 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yang, M. & Vousden, K. H. Serine and one-carbon metabolism in cancer. Nat. Rev. Cancer 16, 650–662 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Maddocks, O. D. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Maddocks, O. D. K. et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544, 372–376 (2017).

    Article  CAS  PubMed  Google Scholar 

  60. Lane, A. N. & Fan, T. W. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 43, 2466–2485 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Garcia-Bermudez, J. et al. Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. Nat. Cell Biol. 20, 775–781 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Birsoy, K. et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540–551 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sullivan, L. B. et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162, 552–563 (2015). Birsoy et al. (2015) and Sullivan et al. (2015) demonstrate that a major function of the mitochondrial ETC is to support aspartate production.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lauren, P. et al. Mitochondrial complex III is necessary for endothelial cell proliferation during angiogenesis. Nat. Metab. 1, 158–171 (2019).

    Article  CAS  Google Scholar 

  65. Liu, X. et al. Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation. Nat. Cell Biol. 19, 626–638 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Weinberg, S. E. et al. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 565, 495–499 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Alistar, A. et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 18, 770–778 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Molina, J. R. et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat. Med. 24, 1036–1046 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. Sullivan, L. B. et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nat. Cell Biol. 20, 782–788 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Swanson, J. A. Shaping cups into phagosomes and macropinosomes. Nat. Rev. Mol. Cell Biol. 9, 639–649 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Recouvreux, M. V. & Commisso, C. Macropinocytosis: a metabolic adaptation to nutrient stress in cancer. Front. Endocrinol. 8, 261 (2017).

    Article  Google Scholar 

  72. Finicle, B. T., Jayashankar, V. & Edinger, A. L. Nutrient scavenging in cancer. Nat. Rev. Cancer 18, 619–633 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Bloomfield, G. & Kay, R. R. Uses and abuses of macropinocytosis. J. Cell Sci. 129, 2697–2705 (2016).

    CAS  PubMed  Google Scholar 

  74. Haigler, H. T., McKanna, J. A. & Cohen, S. Rapid stimulation of pinocytosis in human carcinoma cells A-431 by epidermal growth factor. J. Cell Biol. 83, 82–90 (1979).

    Article  CAS  PubMed  Google Scholar 

  75. Palm, W., Araki, J., King, B., DeMatteo, R. G. & Thompson, C. B. Critical role for PI3-kinase in regulating the use of proteins as an amino acid source. Proc. Natl Acad. Sci. USA 114, E8628–E8636 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bar-Sagi, D. & Feramisco, J. R. Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science 233, 1061–1068 (1986).

    Article  CAS  PubMed  Google Scholar 

  77. Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013). This study shows that macropinocytosis promotes the use of extracellular protein as an amino acid source in RAS-transformed cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Palm, W. et al. The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1. Cell 162, 259–270 (2015). This work demonstrates that mTORC1 activity suppresses the use of extracellular protein as an amino acid source through macropinocytosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Garcia, D. & Shaw, R. J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66, 789–800 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kim, S. M. et al. PTEN deficiency and AMPK activation promote nutrient scavenging and anabolism in prostate cancer cells. Cancer Discov. 8, 866–883 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Nofal, M., Zhang, K., Han, S. & Rabinowitz, J. D. mTOR inhibition restores amino acid balance in cells dependent on catabolism of extracellular protein. Mol. Cell 67, 936–946 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Goldberg, I. J., Eckel, R. H. & Abumrad, N. A. Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways. J. Lipid Res. 50, S86–S90 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  84. Zaidi, N. et al. Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog. Lipid Res. 52, 585–589 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 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).

    CAS  PubMed  Google Scholar 

  86. Gansler, T. S., Hardman, W. 3rd, Hunt, D. A., Schaffel, S. & Hennigar, R. A. Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. Hum. Pathol. 28, 686–692 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Sebastiani, V. et al. Fatty acid synthase is a marker of increased risk of recurrence in endometrial carcinoma. Gynecol. Oncol. 92, 101–105 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Visca, P. et al. Fatty acid synthase (FAS) is a marker of increased risk of recurrence in lung carcinoma. Anticancer Res. 24, 4169–4173 (2004).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Zhang, M. et al. Adipocyte-derived lipids mediate melanoma progression via FATP proteins. Cancer Discov. 8, 1006–1025 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sounni, N. E. et al. Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab. 20, 280–294 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Hochachka, P. W., Rupert, J. L., Goldenberg, L., Gleave, M. & Kozlowski, P. Going malignant: the hypoxia-cancer connection in the prostate. Bioessays 24, 749–757 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Ackerman, D. & Simon, M. C. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol. 24, 472–478 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang, Z., Dales, N. A. & Winther, M. D. Opportunities and challenges in developing stearoyl-coenzyme A desaturase-1 inhibitors as novel therapeutics for human disease. J. Med. Chem. 57, 5039–5056 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Igal, R. A. Stearoyl CoA desaturase-1: new insights into a central regulator of cancer metabolism. Biochim. Biophys. Acta 1861, 1865–1880 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ackerman, D. et al. Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation. Cell Rep. 24, 2596–2605 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Vriens, K. et al. Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity. Nature 566, 403–406 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  100. Nosal, J. M., Switzer, R. L. & Becker, M. A. Overexpression, purification, and characterization of recombinant human 5-phosphoribosyl-1-pyrophosphate synthetase isozymes I and II. J. Biol. Chem. 268, 10168–10175 (1993).

    Article  CAS  PubMed  Google Scholar 

  101. Qian, X. et al. Conversion of PRPS hexamer to monomer by AMPK-mediated phosphorylation inhibits nucleotide synthesis in response to energy stress. Cancer Discov. 8, 94–107 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Graves, L. M. et al. Regulation of carbamoyl phosphate synthetase by MAP kinase. Nature 403, 328–332 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Sigoillot, F. D. et al. Nuclear localization and mitogen-activated protein kinase phosphorylation of the multifunctional protein CAD. J. Biol. Chem. 280, 25611–25620 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Ben-Sahra, I., Howell, J. J., Asara, J. M. & Manning, B. D. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323–1328 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Robitaille, A. M. et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339, 1320–1323 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Wang, Y. & Hekimi, S. Understanding ubiquinone. Trends Cell Biol. 26, 367–378 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. White, R. M. et al. DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature 471, 518–522 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sykes, D. B. et al. Inhibition of dihydroorotate dehydrogenase overcomes differentiation blockade in acute myeloid leukemia. Cell 167, 171–186 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ducker, G. S. & Rabinowitz, J. D. One-carbon metabolism in health and disease. Cell Metab. 25, 27–42 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M. & Manning, B. D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351, 728–733 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Boeynaems, J. M. & Communi, D. Modulation of inflammation by extracellular nucleotides. J. Invest. Dermatol. 126, 943–944 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Scheibner, K. A. et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J. Immunol. 177, 1272–1281 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Singer, A. J. & Clark, R. A. Cutaneous wound healing. N. Engl. J. Med. 341, 738–746 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Dvorak, H. F. Tumors: wounds that do not heal-redux. Cancer Immunol. Res. 3, 1–11 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Sullivan, W. J. et al. Extracellular matrix remodeling regulates glucose metabolism through TXNIP destabilization. Cell 175, 117–132 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Camps, J. L. et al. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc. Natl Acad. Sci. USA 87, 75–79 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  Google Scholar 

  120. Curtis, M. et al. Fibroblasts mobilize tumor cell glycogen to promote proliferation and metastasis. Cell Metab. 29, 141–155 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  121. Keith, B. & Simon, M. C. Hypoxia-inducible factors, stem cells, and cancer. Cell 129, 465–472 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Trabold, O. et al. Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen. 11, 504–509 (2003).

    Article  PubMed  Google Scholar 

  123. Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Pan, M. et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18, 1090–1101 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Muranen, T. et al. Starved epithelial cells uptake extracellular matrix for survival. Nat. Commun. 8, 13989 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Olivares, O. et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat. Commun. 8, 16031 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Katheder, N. S. & Rusten, T. E. Microenvironment and tumors-a nurturing relationship. Autophagy 13, 1241–1243 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016). This work shows that autophagic degradation and release of cellular constituents in pancreatic stellate cells can support the growth of pancreatic cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498–1503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Rabinowitz, J. D. & White, E. Autophagy and metabolism. Science 330, 1344–1348 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Kaur, J. & Debnath, J. Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16, 461–472 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Wyant, G. A. et al. NUFIP1 is a ribosome receptor for starvation-induced ribophagy. Science 360, 751–758 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Amaravadi, R., Kimmelman, A. C. & White, E. Recent insights into the function of autophagy in cancer. Genes Dev. 30, 1913–1930 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Karsli-Uzunbas, G. et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 4, 914–927 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Guo, J. Y. et al. Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes Dev. 30, 1704–1717 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Yang, A. et al. Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms. Cancer Discov. 8, 276–287 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Poillet-Perez, L. et al. Autophagy maintains tumour growth through circulating arginine. Nature 563, 569–573 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Allen, E. L. et al. Differential aspartate usage identifies a subset of cancer cells particularly dependent on OGDH. Cell Rep. 17, 876–890 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. Ilic, N. et al. PIK3CA mutant tumors depend on oxoglutarate dehydrogenase. Proc. Natl Acad. Sci. USA 114, E3434–E3443 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ye, J. et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4, 1406–1417 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Muir, A. et al. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. eLife 6, e27713 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Shin, C. S. et al. The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility. Nat. Commun. 8, 15074 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Kong, H. & Chandel, N. S. Regulation of redox balance in cancer and T cells. J. Biol. Chem. 293, 7499–7507 (2018).

    Article  CAS  PubMed  Google Scholar 

  146. Tonks, N. K. Redox redux: revisiting PTPs and the control of cell signaling. Cell 121, 667–670 (2005).

    Article  CAS  PubMed  Google Scholar 

  147. Tormos, K. V. et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab. 14, 537–544 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Harris, I. S. et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27, 211–222 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015). This work demonstrates that melanoma cells need to overcome the oxidative stress barrier in order to successfully metastasize.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Luengo, A., Gui, D. Y. & Vander Heiden, M. G. Targeting metabolism for cancer therapy. Cell Chem. Biol. 24, 1161–1180 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Parker, W. B. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem. Rev. 109, 2880–2893 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Manning, B. D. & Toker, A. AKT/PKB signaling: navigating the network. Cell 169, 381–405 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank members of the Thompson laboratory for critical discussions during manuscript preparation. J.Z. is supported by the Leukemia and Lymphoma Society postdoctoral fellowship.

Reviewer information

Nature Reviews Molecular Cell Biology thanks N. Chandel, D. Sabatini, and other anonymous reviewer(s), for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jiajun Zhu & Craig B. Thompson

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  1. Jiajun Zhu
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The authors contributed equally to all aspects of the article.

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Correspondence to Craig B. Thompson.

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Competing interests

C.B.T. is a founder of Agios Pharmaceuticals and a member of its scientific advisory board. He is also a former member of the Board of Directors and stockholder of Merck and Charles River Laboratories. He has patents related to cellular metabolism.

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Glossary

Non-essential amino acids

(NEAAs). Amino acids that can be synthesized endogenously and often participate in processes beyond protein translation, such as nucleotide synthesis.

Anaplerosis

The set of biochemical reactions that replenish the intermediates of metabolic pathways.

Minimal medium

Medium that contains the minimum nutrients possible for the growth of cells.

Positron-emission-tomography-based imaging

An imaging technique used clinically to observe metabolic processes for disease diagnosis or monitoring.

p70S6 kinase 1

(S6K1). A kinase downstream of the mTOR complex 1 signalling pathway, the activation of which can lead to increased protein synthesis.

eIF4E binding protein 1

(4EBP1). A protein translation repressor. Its activity is inhibited by phosphorylation mediated by mTOR complex 1 to increase protein synthesis.

Integrated stress response

A mechanism that usually suppresses general protein synthesis but promotes the expression of specific transcription factors to mediate cellular stress response.

Alternative open reading frames

Different open reading frames within a gene, the transcription of which can lead to different gene products that may assume different biological roles.

Cystine

The oxidized dimer form of the amino acid cysteine.

Endoplasmic reticulum (ER) stress

Cellular stress in the ER that often results from the accumulation of misfolded proteins or a failure to maintain the membrane integrity of the ER.

Lysophospholipids

Derivatives of phospholipids in which one of the two acyl chains is lost.

Sapienate

A fatty acid that is usually a component of the secretion from sebaceous glands in the skin. Sapienate can be synthesized from palmitate by desaturation.

Pentose phosphate pathway

A metabolic pathway parallel to glycolysis that involves the generation of various pentoses including ribose 5-phosphate that functions as a precursor for nucleotide synthesis.

One-carbon-unit cycle

A group of biochemical reactions that involve the transfer of the one-carbon groups between various molecules such as tetrahydrofolate, S-adenosylmethionine and vitamin B12.

Ubiquinone

A coenzyme that functions as an electron carrier in various biological processes, including the electron transport chain as part of aerobic cellular respiration.

Folate cycle

A group of biochemical reactions occurring in both the cytosolic and mitochondrial compartments that involve the metabolism of folate and its congeners. The folate cycle can provide critical metabolic intermediates for the biosynthesis of macromolecules such as nucleotides.

Antimetabolite

A chemical used in cancer treatment that often interferes with cellular nucleotide synthesis and DNA replication.

5-Fluorouracil

A medication used in cancer treatment primarily by targeting the thymidylate synthase to block thymidine synthesis.

Damage-associated molecular patterns

A group of biomolecules that are enriched upon non-infectious inflammatory responses such as during the process of wound healing.

Thioredoxin

A class of small proteins encoded by the TXN and TXN2 genes that mainly function as cellular antioxidants.

Cancer-associated fibroblasts

(CAFs). Cells derived from normal fibroblasts within the tumour microenvironment that promote cancer development.

Omentum

Layers of peritoneum that surround abdominal organs.

Malate–aspartate shuttle

A biochemical system that translocates electrons from the cytosol into the mitochondria for oxidative phosphorylation; the process involves the exchange of malate and aspartate between the two compartments.

Glutathione

A tripeptide of glutamate, cysteine and glycine that, together with glutathione-utilizing enzymes, functions to maintain cellular redox homeostasis and to detoxify electrophilic compounds such as reactive oxygen species.

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Zhu, J., Thompson, C.B. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol 20, 436–450 (2019). https://doi.org/10.1038/s41580-019-0123-5

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