MTORC2 in the center of cancer metabolic reprogramming

Trends in Endocrinology and Metabolism

Volumn 25, Issue 7, 2014, Pages 364-373

  Masui, Kenta ^a,b   Cavenee, Webster K ^a   Mischel, Paul S ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE   (Japan)

Author keywords

C Myc; Drug resistance; Epigenetics; Glioblastoma; Metabolic reprogramming; MTORC2

Indexed keywords

EPIDERMAL GROWTH FACTOR RECEPTOR 3; GLUTAMINASE; ISOCITRATE DEHYDROGENASE 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; REACTIVE OXYGEN METABOLITE; STEROL REGULATORY ELEMENT BINDING PROTEIN 1; MULTIPROTEIN COMPLEX; TARGET OF RAPAMYCIN KINASE; TOR COMPLEX 2;

DOWNSTREAM PROCESSING; ENZYME METABOLISM; EPIGENETICS; GENE MUTATION; GLIOBLASTOMA; HUMAN; LIPOGENESIS; NONHUMAN; NUCLEAR REPROGRAMMING; ONCOGENE C MYC; PRIORITY JOURNAL; REVIEW; ANIMAL; GENETICS; METABOLISM; MUTATION; NEOPLASM; PHYSIOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; EPIGENOMICS; GLIOBLASTOMA; HUMANS; MULTIPROTEIN COMPLEXES; MUTATION; NEOPLASMS; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84903437266     PISSN: 10432760     EISSN: 18793061     Source Type: Journal    
DOI: 10.1016/j.tem.2014.04.002     Document Type: Review

References (109)

1. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011, 144:646-674.
2. Ward P.S., Thompson C.B. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 2012, 21:297-308.
3. Vander Heiden M.G., et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324:1029-1033.
4. Dang C.V. Links between metabolism and cancer. Genes Dev. 2012, 26:877-890.
5. Ray P.D., et al. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 2012, 24:981-990.
6. Balaban R.S., et al. Mitochondria, oxidants, and aging. Cell 2005, 120:483-495.
7. García-Jiménez C., et al. A new link between diabetes and cancer: enhanced WNT/β-catenin signaling by high glucose. J. Mol. Endocrinol. 2014, 52:R51-R66.
8. Turturro F., et al. Hyperglycemia regulates thioredoxin-ROS activity through induction of thioredoxin-interacting protein (TXNIP) in metastatic breast cancer-derived cells MDA-MB-231. BMC Cancer 2007, 7:96.
9. Cairns R.A., et al. Regulation of cancer cell metabolism. Nat. Rev. Cancer 2011, 11:85-95.
10. DeBerardinis R.J., Cheng T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010, 29:313-324.
11. Baenke F., et al. Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Dis. Model Mech. 2013, 6:1353-1363.
12. Currie E., et al. Cellular fatty acid metabolism and cancer. Cell Metab. 2013, 18:153-161.
13. Griffiths B., et al. Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer Metab. 2013, 1:3.
14. Nieman K.M., et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 2011, 17:1498-1503.
15. Kidani Y., et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 2013, 14:489-499.
16. Thompson C.B. Rethinking the regulation of cellular metabolism. Cold Spring Harb. Symp. Quant. Biol. 2011, 76:23-29.
17. Ciriello G., et al. Emerging landscape of oncogenic signatures across human cancers. Nat. Genet. 2013, 45:1127-1133.
18. Dang C.V. MYC on the path to cancer. Cell 2012, 149:22-35.
19. Kaelin W.G., McKnight S.L. Influence of metabolism on epigenetics and disease. Cell 2013, 153:56-69.
20. Lu C., et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012, 483:474-478.
21. Brennan C.W., et al. The somatic genomic landscape of glioblastoma. Cell 2013, 155:462-477.
22. Babic I., et al. EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab. 2013, 17:1000-1008.
23. Guo D., et al. The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:12932-12937.
24. Masui K., et al. mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab. 2013, 18:726-739.
25. Guo D., et al. EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci. Signal. 2009, 2:Ra82.
26. Cloughesy T.F., et al. Glioblastoma: from molecular pathology to targeted treatment. Annu. Rev. Pathol. 2014, 9:1-25.
27. Cornu M., et al. mTOR in aging, metabolism, and cancer. Curr. Opin. Genet. Dev. 2013, 23:53-62.
28. Howell J.J., et al. A growing role for mTOR in promoting anabolic metabolism. Biochem. Soc. Trans. 2013, 41:906-912.
29. Laplante M., Sabatini D.M. mTOR signaling in growth control and disease. Cell 2012, 149:274-293.
30. Sarbassov D.D., et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005, 307:1098-1101.
31. Tanaka K., et al. Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance. Cancer Discov. 2011, 1:524-538.
32. Shimada K., et al. TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks. Mol. Cell 2013, 51:829-839.
33. Read R.D., et al. A Drosophila model for EGFR-Ras and PI3K-dependent human glioma. PLoS Genet. 2009, 5:e1000374.
34. Alessi D.R., et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr. Biol. 1997, 7:261-269.
35. Iwanami A., et al. Striking the balance between PTEN and PDK1: it all depends on the cell context. Genes Dev. 1997, 23:1699-1704.
36. Pearce L.R., et al. Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem. J. 2011, 436:169-179.
37. Oh W.J., Jacinto E. mTOR complex 2 signaling and functions. Cell Cycle 2011, 10:2305-2316.
38. Oh W.J., et al. mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J. 2010, 29:3939-3951.
39. Zinzalla V., et al. Activation of mTORC2 by association with the ribosome. Cell 2011, 144:757-768.
40. Julien L.A., et al. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol. Cell. Biol. 2010, 30:908-921.
41. Liu P., et al. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signaling to suppress tumorigenesis. Nat. Cell Biol. 2013, 15:1340-1350.
42. Humphrey S.J., et al. Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab. 2013, 17:1009-1020.
43. Liu P., et al. Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity. Protein Cell 2014, 5:171-177.
44. DeBerardinis R.J., et al. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008, 7:11-20.
45. Koppenol W.H., et al. Otto Warburg's contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 2011, 11:325-337.
46. Levine A.J., Puzio-Kuter A.M. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 2010, 330:1340-1344.
47. Dang C.V. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb. Perspect. Med. 2013, 3:a014217.
48. Kress T.R., et al. The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Mol. Cell 2011, 41:445-457.
49. Deprez J., et al. 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. 1997, 272:17269-17275.
50. 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. 2001, 15:1406-1418.
51. Kohn A.D., et al. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J. Biol. Chem. 1996, 271:31372-31378.
52. Hagiwara A., et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 2012, 15:725-738.
53. Dang C.V., et al. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin. Cancer Res. 2009, 15:6479-6483.
54. McFate T., et al. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J. Biol. Chem. 2008, 283:22700-22708.
55. Wang R.H., et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J. Clin. Invest. 2011, 121:4477-4490.
56. Boehmer C., et al. Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB. Biochem. Biophys. Res. Commun. 2003, 306:156-162.
57. Rosario F.J., et al. Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells. J. Physiol. 2013, 591:609-625.
58. Metallo C.M., et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2011, 481:380-384.
59. Mullen A.R. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2011, 481:385-388.
60. Wise D.R., et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. U.S.A. 2011, 108:19611-19616.
61. Lamming D.W., Sabatini D.M. A central role for mTOR in lipid homeostasis. Cell Metab. 2013, 18:465-469.
62. Yuan M., et al. Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J. Biol. Chem. 2012, 287:29579-29588.
63. Cybulski N., et al. mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:9902-9907.
64. Yao Y., et al. BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation. Sci. Signal. 2013, 6:ra2.
65. Jones K.T., et al. Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol. 2009, 7:e60.
66. Soukas A.A., et al. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 2009, 23:496-511.
67. Santos C.R., Schulze A. Lipid metabolism in cancer. FEBS J. 2012, 279:2610-2623.
68. Migita T., et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 2008, 68:8547-8554.
69. Guo D., et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 2011, 2:290-291.
70. Nelson E.R., et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 2013, 342:1094-1098.
71. Brown M.S., Goldstein J.L. Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL. J. Lipid Res. 2009, 50:S15-S27.
72. Düvel K., et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 2010, 39:171-183.
73. Porstmann T., et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008, 8:224-236.
74. Zelcer N., et al. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 2009, 325:100-104.
75. Lunt S.Y., Vander Heiden M.G. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 2011, 27:441-464.
76. Ramos-Montoya A., et al. Pentose phosphate cycle oxidative and nonoxidative balance: a new vulnerable target for overcoming drug resistance in cancer. Int. J. Cancer 2006, 119:2733-2741.
77. Kliegman J.I., et al. Chemical genetics of rapamycin-insensitive TORC2 in S. cerevisiae. Cell Rep. 2013, 5:1725-1736.
78. Schulze A., Harris A.L. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 2012, 491:364-373.
79. Biggs W.H., et al. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc. Natl. Acad. Sci. U.S.A. 1999, 96:7421-7426.
80. Bouchard C., et al. Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins. EMBO J. 2004, 23:2830-2840.
81. Delpuech O., et al. Induction of Mxi1-SR alpha by FOXO3a contributes to repression of Myc-dependent gene expression. Mol. Cell. Biol. 2007, 27:4917-4930.
82. Gan B., et al. FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell 2010, 18:472-484.
83. Peck B., et al. Antagonism between FOXO and MYC regulates cellular powerhouse. Front. Oncol. 2013, 3:96.
84. Chen Z., et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 2012, 483:613-617.
85. 89Zr-transferrin imaging. Nat. Med. 2012, 18:1586-1591.
86. 11C]-glutamine for metabolic imaging of tumors. J. Nucl. Med. 2012, 53:98-105.
87. 11C-acetate. Am. J. Nucl. Med. Mol. Imaging 2012, 2:33-47.
88. 18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers. Cancer Res. 2011, 71:5164-5174.
89. Shi J., et al. Small molecule inhibitors of Myc/Max dimerization and Myc-induced cell transformation. Bioorg. Med. Chem. Lett. 2009, 19:6038-6041.
90. Alderton G.K. Targeting MYC? You BET. Nat. Rev. Cancer 2011, 11:693.
91. Delmore J.E., et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011, 146:904-917.
92. Lu C., Thompson C.B. Metabolic regulation of epigenetics. Cell Metab. 2012, 16:9-17.
93. Turcan S., et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012, 483:479-483.
94. Dang L., et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009, 462:739-744.
95. Xu W., et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 2011, 19:17-30.
96. Chowdhury R., et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011, 12:463-469.
97. Venneti S., Thompson C.B. Metabolic modulation of epigenetics in gliomas. Brain Pathol. 2013, 23:217-221.
98. Yang W., et al. PKM2phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 2012, 150:685-696.
99. Clayton A.L., et al. Enhanced histone acetylation and transcription: a dynamic perspective. Mol. Cell 2006, 23:289-296.
100. 13C]glucose in human brain tumors in vivo. NMR Biomed. 2012, 25:1234-1244.
101. 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. 2012, 15:827-837.
102. Wellen K.E., et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 2009, 324:1076-1080.
103. Gan H.K., et al. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013, 280:5350-5370.
104. Masui K., et al. Molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies. Neuropathol. Appl. Neurobiol. 2012, 38:271-291.
105. Mellinghoff I.K., et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 2005, 353:2012-2024.
106. Nathanson D.A., et al. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 2014, 343:72-76.
107. Locasale J.W., et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 2011, 43:869-874.
108. Possemato R., et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 2011, 476:346-350.
109. Noh S., et al. Expression levels of serine/glycine metabolism-related proteins in triple negative breast cancer tissues. Tumour Biol. 2014, 35:4457-4468.