Skip to main content
Log in

Glutamine: pleiotropic roles in tumor growth and stress resistance

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Tumors and tumor cell lines rapidly consume the amino acid glutamine (Gln) and use it to supply metabolic pathways that support cell growth and proliferation. Much of the research regarding the relationship between glutamine metabolism and cancer is based on the premise that this abundant nutrient represents an important driver of tumor cell anabolism. However, Gln's influence in cell biology and cancer extends far beyond its use as a carbon and nitrogen source for the structural components of dividing cells. Gln is truly a multipurpose nutrient, feeding many additional pathways that boost the ability of cells to communicate with each other and to cope with stress by oncogenic signaling and by the tumor microenvironment. A number of recent reports have highlighted these “non-anabolic” functions of Gln metabolism in regulating cell survival, oxidative stress resistance, signal transduction, and autophagy. Here, we review some of these findings and discuss their relevance to tumor biology and the potential for cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Levine AJ, Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330:1340–1344

    Article  PubMed  CAS  Google Scholar 

  2. DeBerardinis RJ, Cheng T (2009) Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:313–324

    Article  PubMed  Google Scholar 

  3. Reitzer LJ, Wice BM, Kennell D (1979) Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 254:2669–2676

    PubMed  CAS  Google Scholar 

  4. Brand K (1985) Glutamine and glucose metabolism during thymocyte proliferation. Pathways of glutamine and glutamate metabolism. Biochem J 228:353–361

    PubMed  CAS  Google Scholar 

  5. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104:19345–19350

    Article  PubMed  CAS  Google Scholar 

  6. Lemons JM, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I, Pollina EA, Rabitz HA, Rabinowitz JD, Coller HA (2010) Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol 8:e1000514. doi:10.1371/journal.pbio.1000514

    Article  PubMed  Google Scholar 

  7. Yang C, Sudderth J, Dang T, Bachoo RG, McDonald JG, DeBerardinis RJ (2009) Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res 69:7986–7993

    Article  PubMed  CAS  Google Scholar 

  8. Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu H, Yoon SO, Cantley LC, Blenis J (2010) Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol Cell 38:487–499

    Article  PubMed  CAS  Google Scholar 

  9. Eng CH, Abraham RT (2010) Glutaminolysis yields a metabolic by-product that stimulates autophagy. Autophagy 6:968–970

    Article  PubMed  Google Scholar 

  10. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA 107:8788–8793

    Article  PubMed  CAS  Google Scholar 

  11. Wellen KE, Thompson CB (2010) Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell 40:323–332

    Article  PubMed  CAS  Google Scholar 

  12. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458:762–765

    Article  PubMed  CAS  Google Scholar 

  13. Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y (2007) Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 178:93–105

    Article  PubMed  CAS  Google Scholar 

  14. Lora J, Alonso FJ, Segura JA, Lobo C, Marquez J, Mates JM (2004) Antisense glutaminase inhibition decreases glutathione antioxidant capacity and increases apoptosis in Ehrlich ascitic tumour cells. Eur J Biochem 271:4298–4306

    Article  PubMed  CAS  Google Scholar 

  15. Benassi B, Fanciulli M, Fiorentino F, Porrello A, Chiorino G, Loda M, Zupi G, Biroccio A (2006) c-Myc phosphorylation is required for cellular response to oxidative stress. Mol Cell 21:509–519

    Article  PubMed  CAS  Google Scholar 

  16. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105:18782–18787

    Article  PubMed  CAS  Google Scholar 

  17. Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O'Donnell KA, Kim JW, Yustein JT, Lee LA, Dang CV (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25:6225–6234

    Article  PubMed  CAS  Google Scholar 

  18. Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G (2006) DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol Biol Cell 17:1583–1592

    Article  PubMed  CAS  Google Scholar 

  19. Mallette FA, Gaumont-Leclerc MF, Ferbeyre G (2007) The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev 21:43–48

    Article  PubMed  CAS  Google Scholar 

  20. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA (2010) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18:207–219

    Article  PubMed  CAS  Google Scholar 

  21. Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, Gao S, Puigserver P, Brugge JS (2009) Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461:109–113

    Article  PubMed  CAS  Google Scholar 

  22. Shelton LM, Huysentruyt LC, Seyfried TN (2010) Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model. Int J Cancer 127:2478–2485. doi:10.1002/ijc.25431

    Article  PubMed  CAS  Google Scholar 

  23. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci U S A 107:7455–7460

    Article  PubMed  CAS  Google Scholar 

  24. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, Sugano S, Sato E, Nagao T, Yokote K, Tatsuno I, Prives C (2010) Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A 107:7461–7466

    Article  PubMed  CAS  Google Scholar 

  25. Mates JM, Segura JA, Campos-Sandoval JA, Lobo C, Alonso L, Alonso FJ, Marquez J (2009) Glutamine homeostasis and mitochondrial dynamics. Int J Biochem Cell Biol 41:2051–2061

    Article  PubMed  CAS  Google Scholar 

  26. Curthoys NP, Watford M (1995) Regulation of glutaminase activity and glutamine metabolism. Annu Rev Nutr 15:133–159. doi:10.1146/annurev.nu.15.070195.001025

    Article  PubMed  CAS  Google Scholar 

  27. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075

    Article  PubMed  CAS  Google Scholar 

  28. Gibbons JJ, Abraham RT, Yu K (2009) Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin Oncol 36(Suppl 3):S3–S17

    Article  PubMed  CAS  Google Scholar 

  29. Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010) mTOR regulation of autophagy. FEBS Lett 584:1287–1295

    Article  PubMed  CAS  Google Scholar 

  30. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136:521–534

    Article  PubMed  CAS  Google Scholar 

  31. Fuchs BC, Finger RE, Onan MC, Bode BP (2007) ASCT2 silencing regulates mammalian target-of-rapamycin growth and survival signaling in human hepatoma cells. Am J Physiol Cell Physiol 293:C55–C63

    Article  PubMed  CAS  Google Scholar 

  32. Eng CH, Yu K, Lucas J, White E, Abraham RT (2010) Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal 3: ra31

  33. Yu K, Shi C, Toral-Barza L, Lucas J, Shor B, Kim JE, Zhang WG, Mahoney R, Gaydos C, Tardio L, Kim SK, Conant R, Curran K, Kaplan J, Verheijen J, Ayral-Kaloustian S, Mansour TS, Abraham RT, Zask A, Gibbons JJ (2010) Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res 70:621–631

    Article  PubMed  CAS  Google Scholar 

  34. Sakiyama T, Musch MW, Ropeleski MJ, Tsubouchi H, Chang EB (2009) Glutamine increases autophagy under Basal and stressed conditions in intestinal epithelial cells. Gastroenterology 136:924–932

    Article  PubMed  CAS  Google Scholar 

  35. Braissant O (2010) Current concepts in the pathogenesis of urea cycle disorders. Mol Genet Metab 100(Suppl 1):S3–S12

    Article  PubMed  CAS  Google Scholar 

  36. Wilkinson DJ, Smeeton NJ, Watt PW (2010) Ammonia metabolism, the brain and fatigue; revisiting the link. Prog Neurobiol 91:200–219

    Article  PubMed  CAS  Google Scholar 

  37. Butterworth RF (2002) Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 17:221–227

    Article  PubMed  CAS  Google Scholar 

  38. Sontheimer H (2008) A role for glutamate in growth and invasion of primary brain tumors. J Neurochem 105:287–295

    Article  PubMed  CAS  Google Scholar 

  39. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899

    Article  PubMed  CAS  Google Scholar 

  40. Gatenby RA, Smallbone K, Maini PK, Rose F, Averill J, Nagle RB, Worrall L, Gillies RJ (2007) Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer 97:646–653

    Article  PubMed  CAS  Google Scholar 

  41. Moellering RE, Black KC, Krishnamurty C, Baggett BK, Stafford P, Rain M, Gatenby RA, Gillies RJ (2008) Acid treatment of melanoma cells selects for invasive phenotypes. Clin Exp Metastasis 25:411–425. doi:10.1007/s10585-008-9145-7

    Article  PubMed  CAS  Google Scholar 

  42. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942

    PubMed  CAS  Google Scholar 

  43. Palkova Z, Janderova B, Gabriel J, Zikanova B, Pospisek M, Forstova J (1997) Ammonia mediates communication between yeast colonies. Nature 390:532–536. doi:10.1038/37398

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors declare no conflict of interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert T. Abraham.

Additional information

Naval P. Shanware and Andrew R. Mullen contributed equally to this article.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shanware, N.P., Mullen, A.R., DeBerardinis, R.J. et al. Glutamine: pleiotropic roles in tumor growth and stress resistance. J Mol Med 89, 229–236 (2011). https://doi.org/10.1007/s00109-011-0731-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-011-0731-9

Keywords

Navigation