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The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism

Nature Reviews Cancer volume 20, pages 74–88 (2020)Cite this article

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Abstract

The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)–AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.

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Fig. 1: The PI3K–AKT pathway and its major downstream effectors.
Fig. 2: Direct post-translational regulation of metabolic enzymes and processes downstream of the PI3K–AKT pathway.
Fig. 3: Transcriptional control of metabolic processes downstream of AKT signalling.
Fig. 4: Regulation of nucleotide metabolism downstream of the AKT–mTORC1 pathway.
Fig. 5: AKT signalling and control of NADPH production and consumption.
Fig. 6: Interplay between ROS and the PI3K–AKT pathway.

References

  1. 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 

  2. Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Thorpe, L. M., Yuzugullu, H. & Zhao, J. J. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer 15, 7–24 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alessi, D. R. et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15, 6541–6551 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Alessi, D. R. et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr. Biol. 7, 261–269 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307, 1098–1101 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Dummler, B. & Hemmings, B. A. Physiological roles of PKB/Akt isoforms in development and disease. Biochem. Soc. Trans. 35, 231–235 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang, Y. et al. A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations. Cancer Cell 31, 820–832.e3 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134–1140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 169, 361–371 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Valvezan, A. J. & Manning, B. D. Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat. Metab. 1, 321–333 (2019).

    Article  PubMed  Google Scholar 

  14. 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 

  15. Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. & Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785–789 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Embi, N., Rylatt, D. B. & Cohen, P. Glycogen synthase kinase-3 from rabbit skeletal muscle: separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur. J. Biochem. 107, 519–527 (1980).

    Article  CAS  PubMed  Google Scholar 

  17. Frame, S., Cohen, P. & Biondi, R. M. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell 7, 1321–1327 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Sutherland, C. What are the bona fide GSK3 substrates? Int. J. Alzheimers Dis. 2011, 505607 (2011).

    PubMed  PubMed Central  Google Scholar 

  19. Greer, E. L. & Brunet, A. FOXO transcription factors in ageing and cancer. Acta Physiol. 192, 19–28 (2008).

    Article  CAS  Google Scholar 

  20. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Hornsveld, M., Dansen, T. B., Derksen, P. W. & Burgering, B. M. T. Re-evaluating the role of FOXOs in cancer. Semin. Cancer Biol. 50, 90–100 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Lunt, S. Y. & Vander Heiden, M. G. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441–464 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Elstrom, R. L. et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 64, 3892–3899 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Plas, D. R., Talapatra, S., Edinger, A. L., Rathmell, J. C. & Thompson, C. B. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J. Biol. Chem. 276, 12041–12048 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Gottlob, K. et al. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15, 1406–1418 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Edinger, A. L. & Thompson, C. B. Antigen-presenting cells control T cell proliferation by regulating amino acid availability. Proc. Natl Acad. Sci. USA 99, 1107–1109 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Buzzai, M. et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidation. Oncogene 24, 4165–4173 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Augustin, R. The protein family of glucose transport facilitators: it’s not only about glucose after all. IUBMB Life 62, 315–333 (2010).

    CAS  PubMed  Google Scholar 

  31. Adekola, K., Rosen, S. T. & Shanmugam, M. Glucose transporters in cancer metabolism. Curr. Opin. Oncol. 24, 650–654 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Calera, M. R. et al. Insulin increases the association of Akt-2 with Glut4-containing vesicles. J. Biol. Chem. 273, 7201–7204 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Ng, Y., Ramm, G., Lopez, J. A. & James, D. E. Rapid activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3-L1 adipocytes. Cell Metab. 7, 348–356 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Sano, H. et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J. Biol. Chem. 278, 14599–14602 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Eguez, L. et al. Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein. Cell Metab. 2, 263–272 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. Siska, P. J. et al. Suppression of Glut1 and glucose metabolism by decreased Akt/mTORC1 signaling drives T cell impairment in B cell leukemia. J. Immunol. 197, 2532–2540 (2016).

    Article  CAS  PubMed  Google Scholar 

  38. Waldhart, A. N. et al. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin. Cell Rep. 19, 2005–2013 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu, N. et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol. Cell 49, 1167–1175 (2013). Waldhart et al. (2016) and Wu et al. (2013) demonstrate that both AKT (Siska et al.) and AMPK (Wu et al.) phosphorylate TXNIP at the same site (S308) to induce glucose uptake by inhibiting the endocytosis of GLUT1 or GLUT4 in response to growth signals or energy stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Parikh, H. et al. TXNIP regulates peripheral glucose metabolism in humans. PLOS Med. 4, e158 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Hong, S. Y., Yu, F.-X., Luo, Y. & Hagen, T. Oncogenic activation of the PI3K/Akt pathway promotes cellular glucose uptake by downregulating the expression of thioredoxin-interacting protein. Cell Signal. 28, 377–383 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Ancey, P. B., Contat, C. & Meylan, E. Glucose transporters in cancer — from tumor cells to the tumor microenvironment. FEBS J. 285, 2926–2943 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Roberts, D. J., Tan-Sah, V. P., Smith, J. M. & Miyamoto, S. Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J. Biol. Chem. 288, 23798–23806 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pastorino, J. G., Shulga, N. & Hoek, J. B. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J. Biol. Chem. 277, 7610–7618 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Majewski, N., Nogueira, V., Robey, R. B. & Hay, N. Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol. Cell Biol. 24, 730–740 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Majewski, N. et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16, 819–830 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Liu, Y. et al. Prognostic significance of the metabolic marker hexokinase-2 in various solid tumors: a meta-analysis. PLOS ONE 11, e0166230 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Wolf, A. et al. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J. Exp. Med. 208, 313–326 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Anderson, M., Marayati, R., Moffitt, R. & Yeh, J. J. Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer. Oncotarget 8, 56081–56094 (2017).

    PubMed  Google Scholar 

  50. Patra, K. C. et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24, 213–228 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. DeWaal, D. et al. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat. Commun. 9, 2539 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Wang, L. et al. Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep. 8, 1461–1474 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nogueira, V., Patra, K. C. & Hay, N. Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation. eLife 7, e32213 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Raez, L. E. et al. A phase I dose-escalation trial of 2-deoxy-d-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 71, 523–530 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Deprez, J., Vertommen, D., Alessi, D. R., Hue, L. & Rider, M. H. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J. Biol. Chem. 272, 17269–17275 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Hue, L. & Rider, M. H. Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues. Biochem. J. 245, 313–324 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Houddane, A. et al. Role of Akt/PKB and PFKFB isoenzymes in the control of glycolysis, cell proliferation and protein synthesis in mitogen-stimulated thymocytes. Cell Signal. 34, 23–37 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Miralpeix, M., Azcon-Bieto, J., Bartrons, R. & Argiles, J. M. The impairment of respiration by glycolysis in the Lewis lung carcinoma. Cancer Lett. 50, 173–178 (1990).

    Article  CAS  PubMed  Google Scholar 

  60. Nissler, K., Petermann, H., Wenz, I. & Brox, D. Fructose 2,6-bisphosphate metabolism in Ehrlich ascites tumour cells. J. Cancer Res. Clin. Oncol. 121, 739–745 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. Hu, H. et al. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell 164, 433–446 (2016). This study demonstrates a new mode of regulation of glycolytic flux by PI3K through an AKT-independent, RAC-dependent mechanism involving cytoskeletal remodelling and release of actin-bound aldolase A.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jiang, Z., Wang, X., Li, J., Yang, H. & Lin, X. Aldolase A as a prognostic factor and mediator of progression via inducing epithelial-mesenchymal transition in gastric cancer. J. Cell Mol. Med. 22, 4377–4386 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dai, L. et al. High expression of ALDOA and DDX5 are associated with poor prognosis in human colorectal cancer. Cancer Manag. Res. 10, 1799–1806 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Grandjean, G. et al. Definition of a novel feed-forward mechanism for glycolysis — HIF1α signaling in hypoxic tumors highlights aldolase A as a therapeutic target. Cancer Res. 76, 4259–4269 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Du, S. et al. Fructose-bisphosphate aldolase A is a potential metastasis-associated marker of lung squamous cell carcinoma and promotes lung cell tumorigenesis and migration. PLOS One 9, e85804 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Chae, Y. C. et al. Mitochondrial akt regulation of hypoxic tumor reprogramming. Cancer Cell 30, 257–272 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Düvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Zhong, H. et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 60, 1541–1545 (2000).

    CAS  PubMed  Google Scholar 

  70. Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell Biol. 22, 7004–7014 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat. Med. 10, 594–601 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C. & Semenza, G. L. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell Biol. 21, 3995–4004 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Thomas, G. V. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat. Med. 12, 122–127 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Arsham, A. M., Plas, D. R., Thompson, C. B. & Simon, M. C. Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis. Cancer Res. 64, 3500–3507 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A. L. & Dang, C. V. MYC, metabolism, and cancer. Cancer Discov. 5, 1024–1039 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. West, M. J., Stoneley, M. & Willis, A. E. Translational induction of the c-myc oncogene via activation of the FRAP/TOR signalling pathway. Oncogene 17, 769–780 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Csibi, A. et al. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Curr. Biol. 24, 2274–2280 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Welcker, M. et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc. Natl Acad. Sci. USA 101, 9085–9090 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gregory, M. A., Qi, Y. & Hann, S. R. Phosphorylation by glycogen synthase kinase-3 controls c-Myc proteolysis and subnuclear localization. J. Biol. Chem. 278, 51606–51612 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Sears, R. et al. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 14, 2501–2514 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhang, W. et al. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J. Biol. Chem. 281, 10105–10117 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Jensen, K. S. et al. FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function. EMBO J. 30, 4554–4570 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bouchard, C., Marquardt, J., Brás, A., Medema, R. H. & Eilers, M. Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins. EMBO. J. 23, 2830–2840 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kress, T. R. et al. The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Mol. Cell 41, 445–457 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Wiegering, A. et al. Targeting translation initiation bypasses signaling crosstalk mechanisms that maintain high MYC levels in colorectal cancer. Cancer Discov. 5, 768–781 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Brondfield, S. et al. Direct and indirect targeting of MYC to treat acute myeloid leukemia. Cancer Chemother. Pharmacol. 76, 35–46 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Safaroghli-Azar, A., Bashash, D., Kazemi, A., Pourbagheri-Sigaroodi, A. & Momeny, M. Anticancer effect of pan-PI3K inhibitor on multiple myeloma cells: shedding new light on the mechanisms involved in BKM120 resistance. Eur. J. Pharmacol. 842, 89–98 (2019).

    Article  CAS  PubMed  Google Scholar 

  88. DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. 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 

  90. Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA 105, 18782–18787 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Röhrig, F. & Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16, 732–749 (2016).

    Article  PubMed  CAS  Google Scholar 

  92. 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 

  93. Berwick, D. C., Hers, I., Heesom, K. J., Moule, S. K. & Tavare, J. M. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J. Biol. Chem. 277, 33895–33900 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Potapova, I. A., El-Maghrabi, M. R., Doronin, S. V. & Benjamin, W. B. Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity: allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 39, 1169–1179 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014). This study demonstrates that active AKT promotes ACLY-dependent histone acetylation in cancer cells and in mouse models of breast and pancreatic cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Carrer, A. et al. Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov. 9, 416–435 (2019). This study reveals that KRAS promotes acetyl-CoA abundance to regulate histone acetylation and support the mevalonate pathway for cholesterol biosynthesis, and that loss of ACLY in the pancreas results in the suppression of KRAS-driven pancreatic tumorigenesis.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  99. Khwairakpam, A. D. et al. ATP citrate lyase (ACLY): a promising target for cancer prevention and treatment. Curr. Drug Targets 16, 156–163 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. Ray, K. K. et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N. Engl. J. Med. 380, 1022–1032 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Granchi, C. ATP citrate lyase (ACLY) inhibitors: an anti-cancer strategy at the crossroads of glucose and lipid metabolism. Eur. J. Med. Chem. 157, 1276–1291 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. Wei, J. et al. An allosteric mechanism for potent inhibition of human ATP-citrate lyase. Nature 568, 566–570 (2019).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  106. Yecies, J. L. et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 14, 21–32 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Owen, J. L. et al. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc. Natl Acad. Sci. USA 109, 16184–16189 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ricoult, S. J. H., Yecies, J. L., Ben-Sahra, I. & Manning, B. D. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene 35, 1250–1260 (2016).

    Article  CAS  PubMed  Google Scholar 

  109. Kim, K. H. et al. Regulatory role of glycogen synthase kinase 3 for transcriptional activity of ADD1/SREBP1c. J. Biol. Chem. 279, 51999–52006 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  111. Gouw, A. M. et al. The MYC oncogene cooperates with sterol-regulated element-binding protein to regulate lipogenesis essential for neoplastic growth. Cell Metab. 30, 556–572.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lee, G. et al. Post-transcriptional regulation of de novo lipogenesis by mTORC1–S6K1–SRPK2 signaling. Cell 171, 1545–1558 (2017). This study shows that S6K1 phosphorylates and activates SRPK2 to induce the efficient splicing and translation of mRNAs encoding lipogenic enzymes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Da Silva, M. R. et al. Splicing regulators and their roles in cancer biology and therapy. Biomed. Res. Int. 2015, 150514 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tong, X., Zhao, F. & Thompson, C. B. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr. Opin. Genet. Dev. 19, 32–37 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Villa, E., Ali, E. S., Sahu, U. & Ben-Sahra, I. Cancer cells tune the signaling pathways to empower de novo synthesis of nucleotides. Cancers 11 E688 (2019).

    Google Scholar 

  117. Saha, A. et al. Akt phosphorylation and regulation of transketolase is a nodal point for amino acid control of purine synthesis. Mol. Cell 55, 264–276 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Juvekar, A. et al. Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion. Proc. Natl Acad. Sci. USA 113, E4338–E4347 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ju, H. Q. et al. Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer. Oncogene 36, 6282–6292 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Cascante, M., Centelles, J. J., Veech, R. L., Lee, W. N. & Boros, L. G. Role of thiamin (vitamin B-1) and transketolase in tumor cell proliferation. Nutr. Cancer 36, 150–154 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Kowalik, M. A., Columbano, A. & Perra, A. Emerging role of the pentose phosphate pathway in hepatocellular carcinoma. Front. Oncol. 7, 87 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Patra, K. C. & Hay, N. The pentose phosphate pathway and cancer. Trends Biochem. Sci. 39, 347–354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Schmale Iii, D. G. et al. Genetic structure of atmospheric populations of Gibberella zeae. Phytopathology 96, 1021–1026 (2006).

    Article  PubMed  CAS  Google Scholar 

  124. Liu, Y.-C. et al. Global regulation of nucleotide biosynthetic genes by c-Myc. PLOS ONE 3, e2722 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Mannava, S. et al. Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells. Cell Cycle 7, 2392–2400 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Cunningham, J. T., Moreno, M. V., Lodi, A., Ronen, S. M. & Ruggero, D. Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 157, 1088–1103 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 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 

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

    Article  CAS  PubMed  Google Scholar 

  130. 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). Ben-Sahra et al. (2013), Robitaille et al. (2013) and Ben-Sahra et al. (2016) demonstrate that mTORC1 induces de novo nucleotide synthesis. Ben-Sahra et al. (2013) and Robitaille et al. (2013) reveal that CAD, the enzyme that catalyses the first three steps of the de novo pyrimidine synthesis pathway, is directly phosphorylated by S6K1 to stimulate pyrimidine synthesis. Ben-Sahra et al. (2016) show that mTORC1 enhances purine synthesis through transcriptional mechanisms, including ATF4-mediated induction of the mitochondrial tetrahydrofolate cycle enzyme MTHFD2, which contributes one-carbon units to the formation of the purine ring.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Iadevaia, V., Liu, R. & Proud, C. G. mTORC1 signaling controls multiple steps in ribosome biogenesis. Semin. Cell Dev. Biol. 36, 113–120 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Van Riggelen, J., Yetil, A. & Felsher, D. W. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat. Rev. Cancer 10, 301–309 (2010).

    Article  PubMed  CAS  Google Scholar 

  133. Chabner, B. A. & Roberts, T. G. Timeline: chemotherapy and the war on cancer. Nat. Rev. Cancer 5, 65–72 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Valvezan, A. J. et al. mTORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability. Cancer Cell 32, 624–638.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Huang, F. et al. Inosine monophosphate dehydrogenase dependence in a subset of small cell lung cancers. Cell Metab. 28, 369–382.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Hoxhaj, G. et al. The mTORC1 signaling network senses changes in cellular purine nucleotide levels. Cell Rep. 21, 1331–1346 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Emmanuel, N. et al. Purine nucleotide availability regulates mTORC1 activity through the RHEB GTPase. Cell Rep. 19, 2665–2680 (2017).

    Article  CAS  PubMed  Google Scholar 

  138. Truitt, M. L. & Ruggero, D. New frontiers in translational control of the cancer genome. Nat. Rev. Cancer 17, 332 (2016).

    Article  CAS  PubMed  Google Scholar 

  139. Pourdehnad, M. et al. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc. Natl Acad. Sci. USA 110, 11988–11993 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Schieber, M. & Chandel, N. S. ROS function in redox signaling and oxidative stress. Curr. Biol. 24, R453–R462 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Nilsson, R. et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat. Commun. 5, 3128 (2014).

    Article  PubMed  CAS  Google Scholar 

  142. Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572–583 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lewis, C. A. et al. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell 55, 253–263 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Fan, J. et al. Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510, 298–302 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen, L. et al. NADPH production by the oxidative pentose–phosphate pathway supports folate metabolism. Nat. Metab. 1, 404–415 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Cory, J. G. & Sato, A. Regulation of ribonucleotide reductase activity in mammalian cells. Mol. Cell Biochem. 53–54, 257–266 (1983).

    PubMed  Google Scholar 

  147. Tanner, J. J., Fendt, S.-M. & Becker, D. F. The proline cycle as a potential cancer therapy target. Biochemistry 57, 3433–3444 (2018).

    Article  CAS  PubMed  Google Scholar 

  148. Shimomura, I., Shimano, H., Korn, B. S., Bashmakov, Y. & Horton, J. D. Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J. Biol. Chem. 273, 35299–35306 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. Jiang, P., Du, W., Mancuso, A., Wellen, K. E. & Yang, X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493, 689–693 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Jiang, P. et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat. Cell Biol. 13, 310–316 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ricoult, S. J. H., Dibble, C. C., Asara, J. M. & Manning, B. D. Sterol regulatory element binding protein regulates the expression and metabolic functions of wild-type and oncogenic IDH1. Mol. Cell Biol. 36, 2384–2395 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Charitou, P. et al. FOXOs support the metabolic requirements of normal and tumor cells by promoting IDH1 expression. EMBO Rep. 16, 456–466 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Hoxhaj, G. et al. Direct stimulation of NADP+ synthesis through AKT-mediated phosphorylation of NAD kinase. Science 363, 1088–1092 (2019). This study demonstrates that AKT directly phosphorylates and activates NADK, which generates NADP + from NAD +.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009). This study demonstrates that treatment with antioxidants or activation of oncogenes such as ERBB2, PIK3CA or AKT can rescue ROS-induced cell death caused by detachment of mammary cells from the extracellular matrix.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Tsang, Y. H. et al. Functional annotation of rare gene aberration drivers of pancreatic cancer. Nat. Commun. 7, 10500 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Yau, E. H. et al. Genome-wide CRISPR screen for essential cell growth mediators in mutant Kras colorectal cancers. Cancer Res. 77, 6330–6339 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Thomas, D. C. The phagocyte respiratory burst: historical perspectives and recent advances. Immunol. Lett. 192, 88–96 (2017).

    Article  CAS  PubMed  Google Scholar 

  158. Chen, Q. et al. Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. J. Immunol. 170, 5302–5308 (2003).

    Article  CAS  PubMed  Google Scholar 

  159. Lee, M. Y. et al. Endothelial AKT1 mediates angiogenesis by phosphorylating multiple angiogenic substrates. Proc. Natl Acad. Sci. USA 111, 12865–12870 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wang, W. et al. Superoxide production and reactive oxygen species signaling by endothelial nitric-oxide synthase. J. Biol. Chem. 275, 16899–16903 (2000).

    Article  CAS  PubMed  Google Scholar 

  161. Klotz, L.-O. et al. Redox regulation of FoxO transcription factors. Redox Biol. 6, 51–72 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Kops, G. J. P. L. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316–321 (2002).

    Article  CAS  PubMed  Google Scholar 

  163. Honda, Y. & Honda, S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J. 13, 1385–1393 (1999).

    Article  CAS  PubMed  Google Scholar 

  164. Salmeen, A. et al. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 423, 769–773 (2003).

    Article  CAS  PubMed  Google Scholar 

  165. Lee, S.-R. et al. Reversible inactivation of the tumor suppressor PTEN by H2O2. J. Biol. Chem. 277, 20336–20342 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. Raman, D. & Pervaiz, S. Redox inhibition of protein phosphatase PP2A: potential implications in oncogenesis and its progression. Redox Biol. https://doi.org/10.1016/j.redox.2019.101105 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Leslie, N. R. et al. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J. 22, 5501–5510 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Tonelli, C., Chio, I. I. C. & Tuveson, D. A. Transcriptional regulation by Nrf2. Antioxid. Redox Signal. 29, 1727–1745 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Cullinan, S. B., Gordan, J. D., Jin, J., Harper, J. W. & Diehl, J. A. The Keap1–BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3–Keap1 ligase. Mol. Cell Biol. 24, 8477–8486 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Kobayashi, A. et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell Biol. 24, 7130–7139 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Rada, P. et al. SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol. Cell Biol. 31, 1121–1133 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Li, Y., Dowbenko, D. & Lasky, L. A. AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. J. Biol. Chem. 277, 11352–11361 (2002).

    Article  CAS  PubMed  Google Scholar 

  173. Chen, W. et al. Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol. Cell 34, 663–673 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Lee, S. B., Sellers, B. N. & DeNicola, G. M. The regulation of Nrf2 by nutrient-responsive signaling and its role in anabolic cancer metabolism. Antioxid. Redox Signal. 29, 1774–1791 (2018).

    Article  CAS  PubMed  Google Scholar 

  175. Mitsuishi, Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66–79 (2012). This study demonstrates that the PI3K–AKT pathway promotes nuclear accumulation of NRF2, which stimulates flux into the pentose phosphate pathway and nucleotide synthesis in proliferating cells.

    Article  CAS  PubMed  Google Scholar 

  176. Rojo, A. I. et al. The PTEN/NRF2 axis promotes human carcinogenesis. Antioxid. Redox Signal. 21, 2498–2514 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Lien, E. C. et al. Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer. Nat. Cell Biol. 18, 572–578 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Sasaki, H. et al. Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J. Biol. Chem. 277, 44765–44771 (2002).

    Article  CAS  PubMed  Google Scholar 

  179. Lien, E. C., Ghisolfi, L., Geck, R. C., Asara, J. M. & Toker, A. Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine–glutamate antiporter xCT. Sci. Signal. 10, eaao6604 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Gu, Y. et al. mTORC2 regulates amino acid metabolism in cancer by phosphorylation of the cystine–glutamate antiporter xCT. Mol. Cell 67, 128–138.e7 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Pader, I. et al. Thioredoxin-related protein of 14 kDa is an efficient L-cystine reductase and S-denitrosylase. Proc. Natl Acad. Sci. USA 111, 6964–6969 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol. 15, 273–291 (2018).

    Article  CAS  PubMed  Google Scholar 

  183. Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018). This study demonstrates that systemic hyperinsulinaemia caused by PI3K inhibitors is sufficient to reactivate the PI3K–AKT pathway in tumour models, and that the efficacy of PI3K inhibitors can be improved with anti-glycaemic approaches that prevent hyperinsulinaemia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Ilagan, E. & Manning, B. D. Emerging role of mTOR in the response to cancer therapeutics. Trends Cancer 2, 241–251 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  185. André, F. et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 380, 1929–1940 (2019).

    Article  PubMed  Google Scholar 

  186. Juvekar, A. et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2, 1048–1063 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Konstantinopoulos, P. A. et al. Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 20, 570–580 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. González-Billalabeitia, E. et al. Vulnerabilities of PTEN–TP53-deficient prostate cancers to compound PARP–PI3K inhibition. Cancer Discov. 4, 896–904 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Ma, X. M. & Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10, 307–318 (2009).

    Article  PubMed  CAS  Google Scholar 

  190. Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Hong, S. et al. LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs. eLife 6, e25237 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Lahr, R. M. et al. The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5′TOP sequence. Nucleic Acids Res. 43, 8077–8088 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Fonseca, B. D. et al. La-related protein 1 (LARP1) represses terminal oligopyrimidine (TOP) mRNA translation downstream of mTOR complex 1 (mTORC1). J. Biol. Chem. 290, 15996–16020 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Raught, B. et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 23, 1761–1769 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Holz, M. K., Ballif, B. A., Gygi, S. P. & Blenis, J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123, 569–580 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors apologize to colleagues whose work they were unable to discuss due to space constraints. Research in the Manning lab related to the subject of this review was supported by grants to B.D.M. from the NIH (R35-CA197459 and P01-CA120964), DOD (W81XWH-18-1-0370 and W81XWH-18-1-0659) and a Rothberg Courage Award from the Tuberous Sclerosis Alliance.

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  1. Gerta Hoxhaj

    Present address: Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

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  1. Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Gerta Hoxhaj & Brendan D. Manning

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G.H. and B.D.M. researched and discussed the relevant research literature, wrote the manuscript and drafted the figures.

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B.D.M. is a shareholder and scientific advisory board member of Navitor Pharmaceuticals and LAM Therapeutics. G.H. declares no competing interests.

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Nature Reviews Cancer thanks N. Chandel, A. Di Cristofano and K. E. Wellen for their contribution to the peer review of this work.

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Glossary

Redox homeostasis

Maintaining proper levels of cellular NAD(P)H and NAD(P)+ for metabolic reduction and oxidation reactions, respectively.

Metabolic flexibility

The ability of a cell to adapt its metabolism in response to changing environmental conditions, such as nutrient and energy availability.

Anaplerotic metabolism

Metabolic reactions that replenish tricarboxylic acid (TCA) cycle intermediates used for biosynthetic processes.

Glutaminolysis

The two-step removal of the amide and amine nitrogens from glutamine to produce the TCA cycle intermediate α-ketoglutarate; these reactions can serve as one form of anaplerosis.

Anabolic processes

Metabolic processes and pathways that utilize nutrients and ATP to generate macromolecules such as proteins, lipids and nucleotides.

Quantitative flux analysis

Measurement of the rate of consumption and production of metabolites in specific metabolic pathways, often achieved through the tracing of stable isotope-labelled nutrients and quantification via mass spectrometry.

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Hoxhaj, G., Manning, B.D. The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 20, 74–88 (2020). https://doi.org/10.1038/s41568-019-0216-7

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