Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Tumour metabolism and its unique properties in prostate adenocarcinoma

Abstract

Anabolic metabolism mediated by aberrant growth factor signalling fuels tumour growth and progression. The first biochemical descriptions of the altered metabolic nature of solid tumours were reported by Otto Warburg almost a century ago. Now, the study of tumour metabolism is being redefined by the development of new molecular tools, tumour modelling systems and precise instrumentation together with important advances in genetics, cell biology and spectroscopy. In contrast to Warburg’s original hypothesis, accumulating evidence demonstrates a critical role for mitochondrial metabolism and substantial variation in the way in which different tumours metabolize nutrients to generate biomass. Furthermore, computational and experimental approaches suggest a dominant influence of the tissue-of-origin in shaping the metabolic reprogramming that enables tumour growth. For example, the unique metabolic properties of prostate adenocarcinoma are likely to stem from the distinct metabolism of the prostatic epithelium from which it emerges. Normal prostatic epithelium employs comparatively glycolytic metabolism to sustain physiological citrate secretion, whereas prostate adenocarcinoma consumes citrate to power oxidative phosphorylation and fuel lipogenesis, enabling tumour progression through metabolic reprogramming. Current data suggest that the distinct metabolic aberrations in prostate adenocarcinoma are driven by the androgen receptor, providing opportunities for functional metabolic imaging and novel therapeutic interventions that will be complementary to existing diagnostic and treatment options.

Key points

  • The specific metabolic pathway alterations that enable the anabolic metabolism required for tumour growth differ between cancer types, but mitochondrial metabolism is essential for tumour formation and growth of nearly all tumours.

  • The tissue-of-origin influences tumour metabolism through the combination of tissue-specific protein expression patterns of normal differentiated parenchymal cells and the makeup of the local metabolic microenvironment.

  • Normal prostate metabolism is coordinated by androgen receptor signalling and characterized by a physiological truncation of the tricarboxylic acid cycle to enable the production and secretion of citrate into prostatic fluid.

  • Androgen receptor signalling also controls prostate tumour metabolism, which is characterized by an intact tricarboxylic acid cycle as well as reliance on oxidative phosphorylation and lipogenesis to sustain cellular proliferation.

  • No drugs targeting specific metabolic end points are currently approved for prostate cancer treatment, but multiple agents are in development. Current research to leverage prostate cancer metabolism focuses on functional metabolic imaging to diagnose and monitor the disease.

  • In the future, specific metabolic dependencies generated by androgen receptor signalling in prostate cancer might be exploited for diagnostic and therapeutic benefit in hormone-responsive and castration-resistant disease.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Conventional Warburg metabolism.
Fig. 2: Modern understanding of in vivo tumour metabolism.
Fig. 3: Characteristics of tumour metabolism depend on the tissue of origin.
Fig. 4: Metabolism of a normal prostate epithelial cell.
Fig. 5: Observed and putative prostate adenocarcinoma cell metabolism.

Similar content being viewed by others

References

  1. Vander Heiden, M. G. & DeBerardinis, R. J. Understanding the intersections between metabolism and cancer biology. Cell 168, 657–669 (2017).

    Article  CAS  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 11, 325–337 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Wallace, D. C. Mitochondria and cancer. Nat. Rev. Cancer 12, 685–698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weinberg, S. E. & Chandel, N. S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 11, 9–15 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hoadley, K. A. et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291–304.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hu, J. et al. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat. Biotechnol. 31, 522–529 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Reznik, E. et al. A landscape of metabolic variation across tumor types. Cell Syst. 6, 301–313.e3 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mayers, J. R. & Vander Heiden, M. G. Nature and nurture: what determines tumor metabolic phenotypes? Cancer Res. 77, 3131–3134 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Verze, P., Cai, T. & Lorenzetti, S. The role of the prostate in male fertility, health and disease. Nat. Rev. Urol. 13, 379–386 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Giunchi, F., Fiorentino, M. & Loda, M. The metabolic landscape of prostate cancer. Eur. Urol. Oncol. 2, 28–36 (2019).

    Article  PubMed  Google Scholar 

  13. Warburg, O. & Minami, S. Tests on surviving carcinoma cultures. Biochem. Z. 142, 317–333 (1923).

    CAS  Google Scholar 

  14. Racker, E. Bioenergetics and the problem of tumor growth. Am. Sci. 60, 56–63 (1972).

    CAS  PubMed  Google Scholar 

  15. Earle, W. R. et al. Production of malignancy in vitro. IV. The mouse fibroblast cultures and changes seen in the living cells. J. Natl Cancer Inst. 4, 165–212 (1943).

    CAS  Google Scholar 

  16. Masters, J. R. HeLa cells 50 years on: the good, the bad and the ugly. Nat. Rev. Cancer 2, 315–319 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Jones, H. W. Record of the first physician to see Henrietta Lacks at the Johns Hopkins Hospital: history of the beginning of the HeLa cell line. Am. J. Obstet. Gynecol. 176, S227–S228 (1997).

    Article  PubMed  Google Scholar 

  18. Eagle, H. Nutrition needs of mammalian cells in tissue culture. Science 122, 501–514 (1955).

    Article  CAS  PubMed  Google Scholar 

  19. Shih, C., Shilo, B. Z., Goldfarb, M. P., Dannenberg, A. & Weinberg, R. A. Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin. Proc. Natl Acad. Sci. USA 76, 5714–5718 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Eagle, H. Amino acid metabolism in mammalian cell cultures. Science 130, 432–437 (1959).

    Article  CAS  PubMed  Google Scholar 

  21. Moore, G. E., Gerner, R. E. & Franklin, H. A. Culture of normal human leukocytes. JAMA 199, 519–524 (1967).

    Article  CAS  PubMed  Google Scholar 

  22. Weinhouse, S. On respiratory impairment in cancer cells. Science 124, 267–269 (1956).

    Article  CAS  PubMed  Google Scholar 

  23. Reitzer, L. J., Wice, B. M. & Kennell, D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J. Biol. Chem. 254, 2669–2676 (1979).

    CAS  PubMed  Google Scholar 

  24. Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 619–634 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. DeBerardinis, R. J. & Cheng, T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Berger, T., Saunders, M. E. & Mak, T. W. in Innovative Medicine: Basic Research and Development (eds Nakao, K., Minato, N. & Uemoto, S.) (Springer, 2015).

  27. 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 

  28. Malumbres, M. & Barbacid, M. RAS oncogenes: the first 30 years. Nat. Rev. Cancer 3, 459–465 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Jang, C., Chen, L. & Rabinowitz, J. D. Metabolomics and isotope tracing. Cell 173, 822–837 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wiechert, W. 13C metabolic flux analysis. Metab. Eng. 3, 195–206 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Eagle, H. Metabolic controls in cultured mammalian cells. Science 148, 42–51 (1965).

    Article  CAS  PubMed  Google Scholar 

  32. O’Malley, B. W. Mechanisms of action of steroid hormones. N. Engl. J. Med. 284, 370–377 (1971).

    Article  PubMed  Google Scholar 

  33. DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G. & Thompson, C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. King, M. P. & Attardi, G. Injection of mitochondria into human cells leads to a rapid replacement of the endogenous mitochondrial DNA. Cell 52, 811–819 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Tan, A. S. et al. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab. 21, 81–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Keibler, M. A. et al. Metabolic requirements for cancer cell proliferation. Cancer Metab. 4, 16 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hosios, A. M. et al. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev. Cell 36, 540–549 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lyssiotis, C. A. & Kimmelman, A. C. Metabolic interactions in the tumor microenvironment. Trends Cell Biol. 27, 863–875 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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 

  40. Costello, L. C. & Franklin, R. B. ‘Why do tumour cells glycolyse?’: from glycolysis through citrate to lipogenesis. Mol. Cell. Biochem. 280, 1–8 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Svensson, R. U. et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat. Med. 22, 1108–1119 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fu, A. & Danial, N. N. Grasping for aspartate in tumour metabolism. Nat. Cell Biol. 20, 738–739 (2018).

    Article  CAS  PubMed  Google Scholar 

  44. Sullivan, L. B. et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162, 552–563 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 

  46. Gui, D. Y. et al. Environment dictates dependence on mitochondrial complex I for NAD+ and aspartate production and determines cancer cell sensitivity to metformin. Cell Metab. 24, 716–727 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bertout, J. A., Patel, S. A. & Simon, M. C. The impact of O2 availability on human cancer. Nat. Rev. Cancer 8, 967–975 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sullivan, L. B. et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nat. Cell Biol. 20, 1 (2018).

    Article  CAS  Google Scholar 

  50. Davidson, S. M. et al. Environment impacts the metabolic dependencies of ras-driven non-small cell lung cancer. Cell Metab. 23, 517–528 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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 

  52. Mayers, J. R. & Vander Heiden, M. G. Famine versus feast: understanding the metabolism of tumors in vivo. Trends Biochem. Sci. 40, 130–140 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schulte, M. L. et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat. Med. 24, 194–202 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Marin-Valencia, I. et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab. 15, 827–837 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chen, J. et al. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer. Nat. Genet. 50, 219–228 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Flavin, R., Peluso, S., Nguyen, P. & Loda, M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 6, 551–562 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Chen, M. et al. An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. Nat. Genet. 50, 206–218 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Galluzzi, L., Kepp, O., Vander Heiden, M. G. & Kroemer, G. Metabolic targets for cancer therapy. Nat. Rev. Drug. Discov. 12, 829–846 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  60. Woolthuis, C. M. et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell 19, 23–37 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cheng, C. T. et al. Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction. Commun. Biol. 1, 1–15 (2018).

    Article  CAS  Google Scholar 

  62. Knott, S. R. V. et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554, 378–381 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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 

  64. 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  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kuntz, E. M. et al. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat. Med. 23, 1234–1240 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Davidson, S. M. et al. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat. Med. 23, 235–241 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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 

  68. Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Geller, L. T. et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357, 1156–1160 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Agrawal, V., Alpini, S. E. J., Stone, E. M., Frenkel, E. P. & Frankel, A. E. Targeting methionine auxotrophy in cancer: discovery & exploration. Expert. Opin. Biol. Ther. 12, 53–61 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Phillips, M. M., Sheaff, M. T. & Szlosarek, P. W. Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges. Cancer Res. Treat. 45, 251–262 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Delage, B. et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int. J. Cancer 126, 2762–2772 (2010).

    CAS  PubMed  Google Scholar 

  74. Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hensley, C. T. T. et al. Metabolic heterogeneity in human lung tumors. Cell 164, 681–694 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Faubert, B. et al. Lactate metabolism in human lung tumors. Cell 171, 358–371.e9 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Herbst, E. A. F., George, M. A. J., Brebner, K., Holloway, G. P. & Kane, D. A. Lactate is oxidized outside of the mitochondrial matrix in rodent brain. Appl. Physiol. Nutr. Metab. 43, 467–474 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Chen, Y. J. et al. Lactate metabolism is associated with mammalian mitochondria. Nat. Chem. Biol. 12, 937–943 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bader, D. A. et al. Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. Nat. Metab. 1, 70–85 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Corbet, C. et al. Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects. Nat. Commun. 9, 1208 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tompkins, S. C. et al. Disrupting mitochondrial pyruvate uptake directs glutamine into the TCA cycle away from glutathione synthesis and impairs hepatocellular tumorigenesis article disrupting mitochondrial pyruvate uptake directs glutamine into the TCA cycle away from Glutathi. Cell Rep. 28, 2608–2618.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Park, S. et al. Inhibition of ERRα prevents mitochondrial pyruvate uptake exposing NADPH-generating pathways as targetable vulnerabilities in breast cancer. Cell Rep. 27, 3587–3601.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Courtney, K. D. et al. Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. Cell Metab. 28, 793–800.e2 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cluntun, A. A., Lukey, M. J., Cerione, R. A. & Locasale, J. W. Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer 3, 169–180 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mayers, J. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yuneva, M. O. et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 15, 157–170 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wilson, P. M., Danenberg, P. V., Johnston, P. G., Lenz, H. J. & Ladner, R. D. Standing the test of time: targeting thymidylate biosynthesis in cancer therapy. Nat. Rev. Clin. Oncol. 11, 282–298 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. 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 

  89. Lee, C. H., Akin-Olugbade, O. & Kirschenbaum, A. Overview of prostate anatomy, histology, and pathology. Endocrinol. Metab. Clin. North Am. 40, 565–575 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Ofner, P. Effects and metabolism of hormones in normal and neoplastic prostate tissue. Vitam. Horm. 26, 237–291 (1969).

    Article  Google Scholar 

  91. Bertrand, G. & Vladesco, R. Prostatic zinc concentration. CR Acad. Sci. 173, 176–179 (1921).

    CAS  Google Scholar 

  92. Kolenko, V., Teper, E., Kutikov, A. & Uzzo, R. Zinc and zinc transporters in prostate carcinogenesis. Nat. Rev. Urol. 10, 219–226 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Barron, E. S. G. & Huggins, C. The metabolism of isolated prostatic tissue. J. Urol. 51, 630–634 (1944).

    Article  CAS  Google Scholar 

  94. Barron, E. S. G. & Huggins, C. The metabolism of the prostate: transamination and citric acid. J. Urol. 55, 385–390 (1946).

    Article  CAS  PubMed  Google Scholar 

  95. Costello, L. C. & Franklin, R. B. Aconitase activity, citrate oxidation, and zinc inhibition in rat ventral prostate. Enzyme 26, 281–287 (1981).

    Article  CAS  PubMed  Google Scholar 

  96. Costello, L. C. & Franklin, R. B. The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol. Cancer 5, 17 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Costello, L. C. & Franklin, R. B. Prostate epithelial cells utilize glucose and aspartate as the carbon sources for net citrate production. Prostate 15, 335–342 (1989).

    Article  CAS  PubMed  Google Scholar 

  98. Franklin, R., Ma, J., Zou, J. & Guan, Z. Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells. J. Inorg. Biochem. 96, 435–442 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Franklin, R. B., Zou, J., Yu, Z. & Costello, L. C. EAAC1 is expressed in rat and human prostate epithelial cells; functions as a high-affinity L-aspartate transporter; and is regulated by prolactin and testosterone. BMC Biochem. 7, 10 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kaplan, R. S., Mayor, J. A., Johnston, N. & Oliveira, D. L. Purification and characterization of the reconstitutively active tricarboxylate transporter from rat liver mitochondria. J. Biol. Chem. 265, 13379–13385 (1990).

    CAS  PubMed  Google Scholar 

  101. Mazurek, M. P. et al. Molecular origin of plasma membrane citrate transporter in human prostate epithelial cells. EMBO Rep. 11, 431–437 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bricker, D. K. et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337, 96–100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Herzig, S. et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science 337, 93–96 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Costello, L. C., Akuffo, V. & Franklin, R. B. Testosterone stimulates net citrate production from aspartate by prostate epithelial cells. Horm. Metab. Res. 20, 252–253 (1988).

    Article  CAS  PubMed  Google Scholar 

  105. Costello, L. C. & Franklin, R. B. Concepts of citrate production and secretion by prostate: 2. Hormonal relationships in normal and neoplastic prostate. Prostate 19, 181–205 (1991).

    Article  CAS  PubMed  Google Scholar 

  106. Costello, L. C., Liu, Y., Zou, J. & Franklin, R. B. Evidence for a zinc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone. J. Biol. Chem. 274, 17499–17504 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Lao, L., Franklin, R. B. & Costello, L. C. High-affinity L-aspartate transporter in prostate epithelial cells that is regulated by testosterone. Prostate 22, 53–63 (1993).

    Article  CAS  PubMed  Google Scholar 

  108. Massie, C. E. et al. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J. 30, 2719–2733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Moon, J.-S. et al. Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells. Biochem. J. 433, 225–233 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Costello, L. C. & Franklin, R. B. Testosterone regulates pyruvate dehydrogenase activity of prostate mitochondria. Horm. Metab. Res. 25, 268–270 (1993).

    Article  CAS  PubMed  Google Scholar 

  111. Costello, L. C., Liu, Y., Zou, J. & Franklin, R. B. Mitochondrial aconitase gene expression is regulated by testosterone and prolactin in prostate epithelial cells. Prostate 42, 196–202 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Qian, K., Franklin, R. B. & Costello, L. C. Testosterone regulates mitochondrial aspartate aminotransferase gene expression and mRNA stability in prostate. J. Steroid Biochem. Mol. Biol. 44, 13–19 (1993).

    Article  CAS  PubMed  Google Scholar 

  113. Chang, C. S., Kokontis, J. & Liao, S. T. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 240, 324–326 (1988).

    Article  CAS  PubMed  Google Scholar 

  114. Lubahn, D. B. et al. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 240, 327–330 (1988).

    Article  CAS  PubMed  Google Scholar 

  115. Stelloo, S. et al. Androgen receptor profiling predicts prostate cancer outcome. EMBO Mol. Med. 7, 1450–1464 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Pomerantz, M. M. et al. The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat. Genet. 47, 1346–1351 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nash, C. et al. Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts. Mol. Cell. Endocrinol. 471, 1–14 (2018).

    Article  CAS  PubMed  Google Scholar 

  118. Zadra, G., Photopoulos, C. & Loda, M. The fat side of prostate cancer. Biochim. Biophys. Acta 1831, 1518–1532 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Swinnen, J. V., Van Veldhoven, P. P., Esquenet, M., Heyns, W. & Verhoeven, G. Androgens markedly stimulate the accumulation of neutral lipids in the human prostatic adenocarcinoma cell line LNCaP. Endocrinology 137, 4468–4474 (1996).

    Article  CAS  PubMed  Google Scholar 

  120. Audet-Walsh, É. et al. Androgen-dependent repression of ERRγ reprograms metabolism in prostate cancer. Cancer Res. 77, 378–389 (2017).

    Article  CAS  PubMed  Google Scholar 

  121. Huggins, C. & Hodges, C. V. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1, 293–297 (1941).

    CAS  Google Scholar 

  122. Bader, D. A., Cerne, J. Z. & McGuire, S. E. Recent developments in androgen deprivation therapy for locally advanced prostate cancer. Oncol. Hematol. Rev. 10, 133–138 (2014).

    Google Scholar 

  123. Nuhn, P. et al. Update on systemic prostate cancer therapies: management of metastatic castration-resistant prostate cancer in the era of precision oncology. Eur. Urol. 75, 88–99 (2018).

    Article  PubMed  Google Scholar 

  124. Montgomery, R. B. et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 68, 4447–4454 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Visakorpi, T. et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat. Genet. 9, 401–406 (1995).

    Article  CAS  PubMed  Google Scholar 

  126. Taplin, M. E. et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res. 59, 2511–2515 (1999).

    CAS  PubMed  Google Scholar 

  127. Guo, Z. et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 69, 2305–2313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Stanbrough, M. et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66, 2815–2825 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Dehm, S. M., Schmidt, L. J., Heemers, H. V., Vessella, R. L. & Tindall, D. J. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 68, 5469–5477 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zou, J., Milon, B. C., Desouki, M. M., Costello, L. C. & Franklin, R. B. hZIP1 zinc transporter down-regulation in prostate cancer involves the overexpression of ras responsive element binding protein-1 (RREB-1). Prostate 1524, 1518–1524 (2011).

    Google Scholar 

  131. Desouki, M. M., Geradts, J., Milon, B., Franklin, R. B. & Costello, L. C. hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands. Mol. Cancer 6, 37 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Costello, L. C. & Franklin, R. B. A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer. Arch. Biochem. Biophys. 611, 100–112 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tsouko, E. et al. Regulation of the pentose phosphate pathway by an androgen receptor-mTOR-mediated mechanism and its role in prostate cancer cell growth. Oncogenesis 3, e103 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Putluri, N. et al. Metabolomic profiling reveals a role for androgen in activating amino acid metabolism and methylation in prostate cancer cells. PLoS One 6, e21417 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wang, Q. et al. Targeting amino acid transport in metastatic castration-resistant prostate cancer: effects on cell cycle, cell growth, and tumor development. J. Natl Cancer Inst. 105, 1463–1473 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. White, M. A. et al. Glutamine transporters are targets of multiple oncogenic signaling pathways in prostate cancer. Mol. Cancer Res. 15, 1017–1028 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ono, M. et al. [14 C]Fluciclovine (alias anti-[14 C]FACBC) uptake and ASCT2 expression in castration-resistant prostate cancer cells. Nucl. Med. Biol. 42, 887–892 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Corbin, J. M. & Ruiz-Echevarría, M. J. One-carbon metabolism in prostate cancer: the role of androgen signaling. Int. J. Mol. Sci. 17, E1208 (2016).

    Article  CAS  PubMed  Google Scholar 

  139. Swinnen, J. V., Ulrix, W., Heyns, W. & Verhoeven, G. Coordinate regulation of lipogenic gene expression by androgens: evidence for a cascade mechanism involving sterol regulatory element binding proteins. Proc. Natl Acad. Sci. USA 94, 12975–12980 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Heemers, H. et al. Androgens stimulate lipogenic gene expression in prostate cancer cells by activation of the sterol regulatory element-binding protein cleavage activating protein/sterol regulatory element-binding protein pathway. Mol. Endocrinol. 15, 1817–1828 (2001).

    Article  CAS  PubMed  Google Scholar 

  141. Swinnen, J. V., Esquenet, M., Goossens, K., Heyns, W. & Verhoeven, G. Androgens stimulate fatty acid synthase in the human prostate cancer cell line LNCaP. Cancer Res. 57, 1086–1090 (1997).

    CAS  PubMed  Google Scholar 

  142. Kelly, R. S. et al. The role of tumor metabolism as a driver of prostate cancer progression and lethal disease: results from a nested case-control study. Cancer Metab. 4, 22 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Liu, I. J., Zafar, M. B., Lai, Y.-H., Segall, G. M. & Terris, M. K. Fluorodeoxyglucose positron emission tomography studies in diagnosis and staging of clinically organ-confined prostate cancer. Urology 57, 108–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Spratt, D. E. et al. Utility of FDG-PET in clinical neuroendocrine prostate cancer. Prostate 74, 1153–1159 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kurhanewicz, J., Swanson, M. G., Nelson, S. J. & Vigneron, D. B. Combined magnetic resonance imaging and spectroscopic imaging approach to molecular imaging of prostate cancer. J. Magn. Reson. Imaging 16, 451–463 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Alpha-tocopherol, T., Lung, B. A. & Prevention, C. The ATBC Cancer Prevention Study Group. The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Ann. Epidemiol. 4, 1–10 (1994).

    Google Scholar 

  147. Mondul, A. M. et al. Metabolomic analysis of prostate cancer risk in a prospective cohort: the alpha-tocolpherol, beta-carotene cancer prevention (ATBC) study. Int. J. Cancer 137, 2124–2132 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Nättinen, J. et al. Integrative proteomics in prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression. Nat. Commun. 9, 1176 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Shao, Y. et al. Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer. Int. J. Cancer 143, 396–407 (2018).

    Article  CAS  PubMed  Google Scholar 

  150. Heinz, S. et al. Mechanistic investigations of the mitochondrial complex I inhibitor rotenone in the context of pharmacological and safety evaluation. Sci. Rep. 7, 1–13 (2017).

    Article  CAS  Google Scholar 

  151. Sanchez, M., Gastaldi, L., Remedi, M., Cáceres, A. & Landa, C. Rotenone-induced toxicity is mediated by Rho-GTPases in hippocampal neurons. Toxicol. Sci. 104, 352–361 (2008).

    Article  CAS  PubMed  Google Scholar 

  152. Wheaton, W. W. et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 2014, 1–18 (2014).

    Google Scholar 

  153. Landman, G. W. D. et al. Metformin associated with lower cancer mortality in type 2 diabetes: Zodiac-16. Diabetes Care 33, 322–326 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Margel, D. et al. Association between metformin use and risk of prostate cancer and its grade. J. Natl Cancer Inst. 105, 1123–1131 (2013).

    Article  PubMed  Google Scholar 

  155. Margel, D. et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J. Clin. Oncol. 31, 3069–3075 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Richards, K. A. et al. Metformin use is associated with improved survival for patients with advanced prostate cancer on androgen deprivation therapy. J. Urol. 200, 1256–1263 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  158. Naguib, A. et al. Mitochondrial complex I inhibitors expose a vulnerability for selective killing of pten-null cells. Cell Rep. 23, 58–67 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Jamaspishvili, T. et al. Clinical implications of PTEN loss in prostate cancer. Nat. Rev. Urol. 15, 222–234 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wang, Q. et al. Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res. 71, 7525–7536 (2011).

    Article  CAS  PubMed  Google Scholar 

  161. Yang, C. et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol. Cell 56, 414–424 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Wang, Q. et al. Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. J. Pathol. 236, 278–289 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Savir-Baruch, B., Zanoni, L. & Schuster, D. M. Imaging of prostate cancer using fluciclovine. Urol. Clin. North Am. 45, 489–502 (2018).

    Article  PubMed  Google Scholar 

  165. England, J. R., Paluch, J., Ballas, L. K. & Jadvar, H. 18F-Fluciclovine PET/CT detection of recurrent prostate carcinoma in patients with serum PSA ≤ 1 ng/mL after definitive primary treatment. Clin. Nucl. Med. 44, e128–e132 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Okudaira, H. et al. Accumulation of Trans-1-Amino-3-[18F]Fluorocyclobutanecarboxylic acid in prostate cancer due to androgen-induced expression of amino acid transporters. Mol. Imaging Biol. 16, 756–764 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Nelson, S. J. et al. Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate. Sci. Transl Med. 5, 198ra108 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Granlund, K. L. et al. Hyperpolarized MRI of human prostate cancer reveals increased lactate with tumor grade driven by monocarboxylate transporter 1. Cell Metab. 31, 105–114 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 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 

  170. Zadra, G. & Loda, M. Metabolic vulnerabilities of prostate cancer: diagnostic and therapeutic opportunities. Cold Spring Harb. Perspect. Med. 8, a030569 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Cai, C. et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 71, 6503–6513 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Mason, S. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57–71 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Chypre, M., Zaidi, N. & Smans, K. ATP-citrate lyase: a mini-review. Biochem. Biophys. Res. Commun. 422, 1–4 (2012).

    Article  CAS  PubMed  Google Scholar 

  174. Spick, C., Herrmann, K. & Czernin, J. Evaluation of prostate cancer with 11C-acetate PET/CT. J. Nucl. Med. 57, 30S–37S (2016).

    Article  CAS  PubMed  Google Scholar 

  175. Brown MS, G. J. SREBP pathway: regulation of cholesterol metabolism by proteolysis of membrane bound transcription factor. Cell 89, 331–340 (1997).

    Article  PubMed  Google Scholar 

  176. Zadra, G. et al. Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer. Proc. Natl Acad. Sci. USA 116, 631–640 (2019).

    Article  CAS  PubMed  Google Scholar 

  177. Zadra, G. et al. A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis. EMBO Mol. Med. 6, 519–538 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Garber, K. Cancer anabolic metabolism inhibitors move into clinic. Nat. Biotechnol. 34, 794–795 (2016).

    Article  CAS  PubMed  Google Scholar 

  179. Oyama, N., Akino, H. & Kanamaru, H. 11C-acetate PET imaging of prostate cancer. J. Nucl. Med. 43, 181–186 (2002).

    CAS  PubMed  Google Scholar 

  180. Vāvere, A. L., Kridel, S. J., Wheeler, F. B. & Lewis, J. S. 1-11C-acetate as a PET radiopharmaceutical for imaging fatty acid synthase expression in prostate cancer. J. Nucl. Med. 49, 327–334 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Vinsensia, M. et al. Positron emission tomography (PET) in primary prostate cancer staging and risk assessment. Transl Androl. Urol. 6, 413–423 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Balaban, S. et al. Extracellular fatty acids are the major contributor to lipid synthesis in prostate cancer. Mol. Cancer Res. 17, 949–962 (2019).

    Article  CAS  PubMed  Google Scholar 

  183. Watt, M. J. et al. Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. Sci. Transl Med. 11, eaau5758 (2019).

    Article  CAS  PubMed  Google Scholar 

  184. Lengyel, E., Makowski, L., DiGiovanni, J. & Kolonin, M. G. Cancer as a matter of fat: the crosstalk between adipose tissue and tumors. Trends Cancer 4, 374–384 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Nassar, Z. D. et al. Peri-prostatic adipose tissue: the metabolic microenvironment of prostate cancer. BJU Int. 121, 9–21 (2018).

    Article  PubMed  Google Scholar 

  186. Shi, Y. et al. Androgens promote prostate cancer cell growth through induction of autophagy. Mol. Endocrinol. 27, 280–295 (2013).

    Article  CAS  PubMed  Google Scholar 

  187. Blessing, A. M. et al. Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression. Autophagy 13, 506–521 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  189. 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 

  190. Schulze, A. & Harris, A. L. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 491, 364–373 (2012).

    Article  CAS  PubMed  Google Scholar 

  191. Vander Heiden, M. G. Targeting cancer metabolism: a therapeutic window opens. Nat. Rev. Drug. Discov. 10, 671–684 (2011).

    Article  CAS  Google Scholar 

  192. Danhier, P. et al. Cancer metabolism in space and time: beyond the Warburg effect. Biochim. Biophys. Acta Bioenerg. 1858, 556–572 (2017).

    Article  CAS  PubMed  Google Scholar 

  193. Jiang, L. et al. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255–258 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Massagué, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Seyfried, T. N. et al. Provocative question: should ketogenic metabolic therapy become the standard of care for glioblastoma? Neurochem. Res. 44, 2392–2404 (2019).

    Article  CAS  PubMed  Google Scholar 

  196. Brown, J. S., de Groot, A. E., Pienta, K. J., Amend, S. R. & Roy, S. Revisiting seed and soil: examining the primary tumor and cancer cell foraging in metastasis. Mol. Cancer Res. 15, 361–370 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Zacharakis, N. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724–730 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. D’Aloia, M. M., Zizzari, I. G., Sacchetti, B., Pierelli, L. & Alimandi, M. CAR-T cells: the long and winding road to solid tumors. Cell Death Dis. 9, 282 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Chowdhury, P. S., Chamoto, K. & Honjo, T. Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy. J. Intern. Med. 283, 110–120 (2018).

    Article  CAS  PubMed  Google Scholar 

  200. Biswas, S. K. Metabolic reprogramming of immune cells in cancer progression. Immunity 43, 435–449 (2015).

    Article  CAS  PubMed  Google Scholar 

  201. Vancura, A., Bu, P., Bhagwat, M., Zeng, J. & Vancurova, I. Metformin as an anticancer agent. Trends Pharmacol. Sci. 39, 867–878 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Whitburn, J., Edwards, C. M. & Sooriakumaran, P. Metformin and prostate cancer: a new role for an old drug. Curr. Urol. Rep. 18, 1–7 (2017).

    Article  Google Scholar 

  203. Zingales, V. et al. Metformin: a bridge between diabetes and prostate cancer. Front. Oncol. 7, 1–7 (2017).

    Article  Google Scholar 

  204. Liu, X., Romero, I. L., Litchfield, L. M., Lengyel, E. & Locasale, J. W. Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers. Cell Metab. 24, 728–739 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Gross, M. I. et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol. Cancer Ther. 13, 890–901 (2014).

    Article  CAS  PubMed  Google Scholar 

  206. Boysen, G. et al. Glutaminase inhibitor CB-839 increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice. Int. J. Radiat. Biol. 95, 436–442 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

D.A.B. is supported by the Baylor College of Medicine Medical Scientist Training Program and NIH grant no. F30CA196108. S.E.M. is supported by the Prostate Cancer Foundation, The Caroline Weiss Law Scholar Foundation, the M.D. Anderson Physician Scientist Development Program and NIH grant no. R21CA205257. We thank members of the Department of Molecular and Cellular Biology at Baylor College of Medicine for productive conversations related to this manuscript.

Author information

Authors and Affiliations

Authors

Contributions

Both authors researched data for the article. D.A.B. wrote the manuscript. Both authors made substantial contributions to discussion of the article content, reviewed the article and edited the manuscript before submission.

Corresponding authors

Correspondence to David A. Bader or Sean E. McGuire.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Urology thanks M. Siddiqui, M. Loda and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bader, D.A., McGuire, S.E. Tumour metabolism and its unique properties in prostate adenocarcinoma. Nat Rev Urol 17, 214–231 (2020). https://doi.org/10.1038/s41585-020-0288-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-020-0288-x

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer