Skip to main content

Advertisement

SpringerLink
Log in

mTOR links oncogenic signaling to tumor cell metabolism

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

Abstract

As a key regulator of cell growth and proliferation, the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) has been the subject of intense investigation for its role in tumor development and progression. This research has revealed a signaling network of oncogenes and tumor suppressors lying upstream of mTORC1, and oncogenic perturbations to this network result in the aberrant activation of this kinase complex in the majority of human cancers. However, the molecular events downstream of mTORC1 contributing to tumor cell growth and proliferation are just coming to light. In addition to its better-known functions in promoting protein synthesis and suppressing autophagy, mTORC1 has emerged as a key regulator of cellular metabolism. Recent studies have found that mTORC1 activation is sufficient to stimulate an increase in glucose uptake, glycolysis, and de novo lipid biosynthesis, which are considered metabolic hallmarks of cancer, as well as the pentose phosphate pathway. Here, we focus on the molecular mechanisms of metabolic regulation by mTORC1 and the potential consequences for anabolic tumor growth and therapeutic strategies.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Menon S, Manning BD (2008) Common corruption of the mTOR signaling network in human tumors. Oncogene 27:S43–S51

    Article  PubMed  CAS  Google Scholar 

  2. Huang J, Manning BD (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412:179–190

    Article  PubMed  CAS  Google Scholar 

  3. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25:903–915

    Article  PubMed  CAS  Google Scholar 

  4. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303

    Article  PubMed  CAS  Google Scholar 

  5. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590

    Article  PubMed  CAS  Google Scholar 

  6. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226

    Article  PubMed  CAS  Google Scholar 

  7. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6:91–99

    Article  PubMed  CAS  Google Scholar 

  8. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484

    Article  PubMed  CAS  Google Scholar 

  9. Bilanges B, Argonza-Barrett R, Kolesnichenko M, Skinner C, Nair M, Chen M, Stokoe D (2007) Tuberous sclerosis complex proteins 1 and 2 control serum-dependent translation in a TOP-dependent and -independent manner. Mol Cell Biol 27:5746–5764

    Article  PubMed  CAS  Google Scholar 

  10. Mayer C, Grummt I (2006) Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 25:6384–6391

    Article  PubMed  CAS  Google Scholar 

  11. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307–318

    Article  PubMed  Google Scholar 

  12. Neufeld TP (2010) TOR-dependent control of autophagy: biting the hand that feeds. Current Opin Cell Biol 22:157–168

    Article  CAS  Google Scholar 

  13. Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev 7:961–967

    Article  CAS  Google Scholar 

  14. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Article  Google Scholar 

  15. Altenberg B, Greulich KO (2004) Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 84:1014–1020

    Article  PubMed  CAS  Google Scholar 

  16. Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269:23757–23763

    PubMed  CAS  Google Scholar 

  17. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL (2000) Modulation of hypoxia-inducible factor 1alpha 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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014

    Article  PubMed  CAS  Google Scholar 

  20. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23:9361–9374

    Article  PubMed  CAS  Google Scholar 

  21. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594–601

    Article  PubMed  CAS  Google Scholar 

  22. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39:171–183

    Article  PubMed  Google Scholar 

  23. West MJ, Stoneley M, Willis AE (1998) Translational induction of the c-myc oncogene via activation of the FRAP/TOR signalling pathway. Oncogene 17:769–780

    Article  PubMed  CAS  Google Scholar 

  24. Gordan JD, Thompson CB, Simon MC (2007) HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12:108–113

    Article  PubMed  CAS  Google Scholar 

  25. Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS, Finkel T (2006) The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 281:27643–27652

    Article  PubMed  CAS  Google Scholar 

  26. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450:736–740

    Article  PubMed  CAS  Google Scholar 

  27. Ramanathan A, Schreiber SL (2009) Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci U S A 106:22229–22232

    Article  PubMed  CAS  Google Scholar 

  28. Bentzinger CF, Romanino K, Cloetta D, Lin S, Mascarenhas JB, Oliveri F, Xia J, Casanova E, Costa CF, Brink M, Zorzato F, Hall MN, Ruegg MA (2008) Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab 8:411–424

    Article  PubMed  CAS  Google Scholar 

  29. Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev 7:763–777

    Article  CAS  Google Scholar 

  30. Raghow R, Yellaturu C, Deng X, Park EA, Elam MB (2008) SREBPs: the crossroads of physiological and pathological lipid homeostasis. Trends Endocrinol Metabol 19:65–73

    Article  CAS  Google Scholar 

  31. Porstmann T, Griffiths B, Chung YL, Delpuech O, Griffiths JR, Downward J, Schulze A (2005) PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 24:6465–6481

    PubMed  CAS  Google Scholar 

  32. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8:224–236

    Article  PubMed  CAS  Google Scholar 

  33. Van de Sande T, De Schrijver E, Heyns W, Verhoeven G, Swinnen JV (2002) Role of the phosphatidylinositol 3′-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Res 62:642–646

    PubMed  Google Scholar 

  34. Van de Sande T, Roskams T, Lerut E, Joniau S, Van Poppel H, Verhoeven G, Swinnen JV (2005) High-level expression of fatty acid synthase in human prostate cancer tissues is linked to activation and nuclear localization of Akt/PKB. J Pathol 206:214–219

    Article  PubMed  Google Scholar 

  35. Guo D, Prins RM, Dang J, Kuga D, Iwanami A, Soto H, Lin KY, Huang TT, Akhavan D, Hock MB, Zhu S, Kofman AA, Bensinger SJ, Yong WH, Vinters HV, Horvath S, Watson AD, Kuhn JG, Robins HI, Mehta MP, Wen PY, DeAngelis LM, Prados MD, Mellinghoff IK, Cloughesy TF, Mischel PS (2009) EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Science Signaling 2:ra82

    Article  PubMed  Google Scholar 

  36. Zampella EJ, Bradley EL Jr, Pretlow TG 2nd (1982) Glucose-6-phosphate dehydrogenase: a possible clinical indicator for prostatic carcinoma. Cancer 49:384–387

    Article  PubMed  CAS  Google Scholar 

  37. Bokun R, Bakotin J, Milasinovic D (1987) Semiquantitative cytochemical estimation of glucose-6-phosphate dehydrogenase activity in benign diseases and carcinoma of the breast. Acta Cytol 31:249–252

    PubMed  CAS  Google Scholar 

  38. Dessi S, Batetta B, Cherchi R, Onnis R, Pisano M, Pani P (1988) Hexose monophosphate shunt enzymes in lung tumors from normal and glucose-6-phosphate-dehydrogenase-deficient subjects. Oncology 45:287–291

    Article  PubMed  CAS  Google Scholar 

  39. Langbein S, Zerilli M, Zur Hausen A, Staiger W, Rensch-Boschert K, Lukan N, Popa J, Ternullo MP, Steidler A, Weiss C, Grobholz R, Willeke F, Alken P, Stassi G, Schubert P, Coy JF (2006) Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer 94:578–585

    Article  PubMed  CAS  Google Scholar 

  40. Krockenberger M, Honig A, Rieger L, Coy JF, Sutterlin M, Kapp M, Horn E, Dietl J, Kammerer U (2007) Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of distant metastases. Int J Gynecol Canc 17:101–106

    Article  CAS  Google Scholar 

  41. Langbein S, Frederiks WM, zur Hausen A, Popa J, Lehmann J, Weiss C, Alken P, Coy JF (2008) Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer. Int J Canc 122:2422–2428

    Article  CAS  Google Scholar 

  42. Amemiya-Kudo M, Shimano H, Hasty AH, Yahagi N, Yoshikawa T, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Sato R, Kimura S, Ishibashi S, Yamada N (2002) Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes. J Lipid Res 43:1220–1235

    PubMed  CAS  Google Scholar 

  43. Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL, Brown MS (2002) Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem 277:9520–9528

    Article  PubMed  CAS  Google Scholar 

  44. Shimomura I, Shimano H, Korn BS, Bashmakov Y, Horton JD (1998) 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

    Article  PubMed  CAS  Google Scholar 

  45. 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 

  46. Guertin DA, Sabatini DM (2009) The pharmacology of mTOR inhibition. Science Signaling 2:pe24

    Article  PubMed  Google Scholar 

  47. 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 

  48. Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning BD, Hotamisligil GS (2008) Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29:541–551

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Research in the Manning laboratory on mTORC1 function in cancer and metabolism is supported in part by grants to B.D.M. from the National Institutes of Health (CA122617; CA120964), Department of Defense (TS093033), and the American Diabetes Association.

Conflict of interest

The authors declare no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Ave, SPH2-117, Boston, MA, 02115, USA

    Jessica L. Yecies & Brendan D. Manning

Authors
  1. Jessica L. Yecies
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brendan D. Manning
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brendan D. Manning.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yecies, J.L., Manning, B.D. mTOR links oncogenic signaling to tumor cell metabolism. J Mol Med 89, 221–228 (2011). https://doi.org/10.1007/s00109-011-0726-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-011-0726-6

Keywords

Search

Navigation