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Metabolic Reprogramming by the PI3K-Akt-mTOR Pathway in Cancer

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Metabolism in Cancer

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 207))

Abstract

In the past decade, there has been a resurgence of interest in elucidating how metabolism is altered in cancer cells and how such dependencies can be targeted for therapeutic gain. At the core of this research is the concept that metabolic pathways are reprogrammed in cancer cells to divert nutrients toward anabolic processes to facilitate enhanced growth and proliferation. Importantly, physiological cellular signaling mechanisms normally tightly regulate the ability of cells to gain access to and utilize nutrients, posing a fundamental barrier to transformation. This barrier is often overcome by aberrations in cellular signaling that drive tumor pathogenesis by enabling cancer cells to make critical cellular decisions in a cell-autonomous manner. One of the most frequently altered pathways in human cancer is the PI3K-Akt-mTOR signaling pathway. Here, we describe mechanisms by which this signaling network is responsible for controlling cellular metabolism. Through both the post-translational regulation and the induction of transcriptional programs, the PI3K-Akt-mTOR pathway coordinates the uptake and utilization of multiple nutrients, including glucose, glutamine, nucleotides, and lipids, in a manner best suited for supporting the enhanced growth and proliferation of cancer cells. These regulatory mechanisms illustrate how metabolic changes in cancer are closely intertwined with oncogenic signaling pathways that drive tumor initiation and progression.

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Abbreviations

PI3K:

Phosphoinositide 3-kinase

mTOR:

Mammalian target of rapamycin

RTKs:

Receptor tyrosine kinases

GPCRs:

G-protein-coupled receptors

PIP3 :

Phosphatidylinositol-3,4,5-trisphosphate

PIP2 :

Phosphatidylinositol-4,5-bisphosphate

PTEN:

Phosphatase and tensin homolog

PH:

Pleckstrin homology

PDK1:

Phosphoinositide-dependent protein kinase 1

mTORC1/2:

Mammalian target of rapamycin complex 1/2

HK:

Hexokinase

PFK1/2:

Phosphofructokinase 1/2

TSC1/2:

Tuberous sclerosis 1/2

GAP:

GTPase-activating protein

S6K1/2:

S6 kinase 1/2

4E-BP1/2:

eIF4E (eukaryotic initiation factor 4E)-binding protein 1/2

FoxO:

Forkhead box O

GSK-3β:

Glycogen synthase kinase-3β

HIF:

Hypoxia-inducible factor

SREBP:

Sterol regulatory element-binding protein

SRE:

Sterol regulatory elements

TXNIP:

Thioredoxin-interacting protein

AMPK:

AMP-dependent protein kinase

18FDG:

18-fluoro-deoxyglucose

PET:

Positron emission tomography

G6P:

Glucose 6-phosphate

VDAC:

Voltage-dependent anion channel

OMM:

Outer mitochondrial membrane

PDK1:

Pyruvate dehydrogenase kinase 1

PDH:

Pyruvate dehydrogenase

TCA:

Tricarboxylic acid

NADH:

Nicotinamide adenine dinucleotide

LDHA:

Lactate dehydrogenase A

GPI:

Glucose phosphate isomerase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

TPI:

Triosephosphate isomerase

PGK1:

Phosphoglycerate kinase 1

ENO1:

Enolase

GCK:

Glucokinase

ALDOB:

Aldolase B

PK1:

Pyruvate kinase 1

PPP:

Pentose phosphate pathway

NADPH:

Nicotinamide adenine dinucleotide phosphate

Ru5P:

Ribulose 5-phosphate

R5P:

Ribose 5-phosphate

F6P:

Fructose 6-phosphate

Ga3P:

Glyceraldehyde 3-phosphate

G6PD:

Glucose 6-phosphate dehydrogenase

TKT:

Transketolase

PGD:

6-phosphogluconate dehydrogenase

RPE:

Ribulose 5-phosphate epimerase

RPIA:

Ribulose 5-phosphate isomerase

TALDO1:

Transaldolase 1

CAD:

Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase

PRPP:

Phosphoribosyl pyrophosphate

ACL:

ATP citrate lyase

αKG:

α-ketoglutarate

GLS:

Glutaminase

GLUL:

Glutamine synthetase

GDH:

Glutamate dehydrogenase

ASNS:

Asparagine synthetase

GFPT1:

Glutamine–fructose 6-phosphate transaminase 1

References

  • Ahn KJ, Hwang HS, Park JH, Bang SH, Kang WJ, Yun M, Lee JD (2009) Evaluation of the role of hexokinase type II in cellular proliferation and apoptosis using human hepatocellular carcinoma cell lines. J Nucl Med 50:1525–1532

    Article  CAS  PubMed  Google Scholar 

  • Alessi DR, Caudwell FB, Andjelkovic M, Hemmings BA, Cohen P (1996) Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett 399:333–338

    Article  CAS  PubMed  Google Scholar 

  • Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261–269

    Article  CAS  PubMed  Google Scholar 

  • Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC (1989) PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57:167–175

    Article  CAS  PubMed  Google Scholar 

  • Bae SS, Cho H, Mu J, Birnbaum MJ (2003) Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J Biol Chem 278:49530–49536

    Article  CAS  PubMed  Google Scholar 

  • Balasubramanian MN, Butterworth EA, Kilberg MS (2013) Asparagine synthetase: regulation by cell stress and involvement in tumor biology. Am J Physiol Endocrinol Metab 304:E789–E799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, Sougnez C, Zou L, Cortes ML, Fernandez-Lopez JC, Peng S, Ardlie KG, Auclair D, Bautista-Pina V, Duke F, Francis J, Jung J, Maffuz-Aziz A, Onofrio RC, Parkin M, Pho NH, Quintanar-Jurado V, Ramos AH, Rebollar-Vega R, Rodriguez-Cuevas S, Romero-Cordoba SL, Schumacher SE, Stransky N, Thompson KM, Uribe-Figueroa L, Baselga J, Beroukhim R, Polyak K, Sgroi DC, Richardson AL, Jimenez-Sanchez G, Lander ES, Gabriel SB, Garraway LA, Golub TR, Melendez-Zajgla J, Toker A, Getz G, Hidalgo-Miranda A, Meyerson M (2012) Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486:405–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bar-Peled L, Sabatini DM (2014) Regulation of mTORC1 by amino acids. Trends Cell Biol 24:400–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bardos JI, Ashcroft M (2004) Hypoxia-inducible factor-1 and oncogenic signalling. BioEssays 26:262–269

    Article  CAS  PubMed  Google Scholar 

  • Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JPJ, Roth RA (1999) Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem 274:20281–20286

    Article  CAS  PubMed  Google Scholar 

  • Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB (2005) ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24:6314–6322

    Article  CAS  PubMed  Google Scholar 

  • Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V, Ferrandina G, Benedetti Panici P, Mancuso S, Neri G, Testa JR (1995) Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64:280–285

    Article  CAS  PubMed  Google Scholar 

  • Bellacosa A, Kumar CC, Di Cristofano A, Testa JR (2005) Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94:29–86

    Article  CAS  PubMed  Google Scholar 

  • Ben-Haim S, Ell P (2009) 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J Nucl Med 50:88–99

    Article  PubMed  Google Scholar 

  • Ben-Sahra I, Howell JJ, Asara JM, Manning BD (2013) Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339:1323–1328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bentley J, Itchayanan D, Barnes K, McIntosh E, Tang X, Downes CP, Holman GD, Whetton AD, Owen-Lynch PJ, Baldwin SA (2003) Interleukin-3-mediated cell survival signals include phosphatidylinositol 3-kinase-dependent translocation of the glucose transporter GLUT1 to the cell surface. J Biol Chem 278:39337–39348

    Article  CAS  PubMed  Google Scholar 

  • Berwick DC, Dell GC, Welsh GI, Heesom KJ, Hers I, Fletcher LM, Cooke FT, Tavare JM (2004) Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles. J Cell Sci 117:5985–5993

    Article  CAS  PubMed  Google Scholar 

  • Berwick DC, Hers I, Heesom KJ, Moule SK, Tavare JM (2002) The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J Biol Chem 277:33895–33900

    Article  CAS  PubMed  Google Scholar 

  • Blancher C, Moore JW, Robertson N, Harris AL (2001) Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3′-kinase/Akt signaling pathway. Cancer Res 61:7349–7355

    CAS  PubMed  Google Scholar 

  • Boehmer C, Okur F, Setiawan I, Broer S, Lang F (2003) Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB. Biochem Biophys Res Commun 306:156–162

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Boormans JL, Korsten H, Ziel-van der Made AC, van Leenders GJ, Verhagen PC, Trapman J (2010) E17K substitution in AKT1 in prostate cancer. Br J Cancer 102:1491–1494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boros LG, Bassilian S, Lim S, Lee WN (2001) Genistein inhibits nonoxidative ribose synthesis in MIA pancreatic adenocarcinoma cells: a new mechanism of controlling tumor growth. Pancreas 22:1–7

    Article  CAS  PubMed  Google Scholar 

  • Boros LG, Puigjaner J, Cascante M, Lee WN, Brandes JL, Bassilian S, Yusuf FI, Williams RD, Muscarella P, Melvin WS, Schirmer WJ (1997) Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation. Cancer Res 57:4242–4248

    CAS  PubMed  Google Scholar 

  • Boss GR, Pilz RB (1985) Phosphoribosylpyrophosphate synthesis from glucose decreases during amino acid starvation of human lymphoblasts. J Biol Chem 260:6054–6059

    CAS  PubMed  Google Scholar 

  • Bouchard C, Marquardt J, Bras A, Medema RH, Eilers M (2004) Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins. EMBO J 23:2830–2840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brahimi-Horn MC, Chiche J, Pouyssegur J (2007) Hypoxia signalling controls metabolic demand. Curr Opin Cell Biol 19:223–229

    Article  CAS  PubMed  Google Scholar 

  • Brunet A, Kanai F, Stehn J, Xu J, Sarbassova D, Frangioni JV, Dalal SN, DeCaprio JA, Greenberg ME, Yaffe MB (2002) 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J Cell Biol 156:817–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681

    Article  CAS  PubMed  Google Scholar 

  • Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657

    Article  CAS  PubMed  Google Scholar 

  • Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439–444

    Article  CAS  PubMed  Google Scholar 

  • Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, Huang HY, Tsai KK, Flores LG, Shao Y, Hazle JD, Yu D, Wei W, Sarbassov D, Hung MC, Nakayama KI, Lin HK (2012) The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 149:1098–1111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan DA, Sutphin PD, Denko NC, Giaccia AJ (2002) Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. J Biol Chem 277:40112–40117

    Article  CAS  PubMed  Google Scholar 

  • Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR (1996) Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 93:3636–3641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chin YR, Yoshida T, Marusyk A, Beck AH, Polyak K, Toker A (2014) Targeting Akt3 signaling in triple-negative breast cancer. Cancer Res 74:964–973

    Article  CAS  PubMed  Google Scholar 

  • Cong LN, Chen H, Li Y, Zhou L, McGibbon MA, Taylor SI, Quon MJ (1997) Physiological role of Akt in insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. Mol Endocrinol 11:1881–1890

    Article  CAS  PubMed  Google Scholar 

  • Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, Henske EP, Haigis MC, Cantley LC, Stephanopoulos G, Yu J, Blenis J (2013) The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153:840–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dang CV (2007) The interplay between MYC and HIF in the Warburg effect. In: Ernst Schering Foundation Symposium Proceedings, pp 35–53

    Google Scholar 

  • Davies MA, Stemke-Hale K, Tellez C, Calderone TL, Deng W, Prieto VG, Lazar AJ, Gershenwald JE, Mills GB (2008) A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer 99:1265–1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de la Cruz-Herrera CF, Campagna M, Lang V, del Carmen González-Santamaría J, Marcos-Villar L, Rodríguez MS, Vidal A, Collado M, Rivas C (2015) SUMOylation regulates AKT1 activity. Oncogene 34:1442–1450

    Article  PubMed  CAS  Google Scholar 

  • Deberardinis RJ, Lum JJ, Thompson CB (2006) Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. J Biol Chem 281:37372–37380

    Article  CAS  PubMed  Google Scholar 

  • Deng X, Zhang W, O-Sullivan I, Williams JB, Dong Q, Park EA, Raghow R, Unterman TG, Elam MB (2012) FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. J Biol Chem 287:20132–20143

    Google Scholar 

  • Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Dessì 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  Google Scholar 

  • Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD (2012) TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 47:535–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dibble CC, Manning BD (2013) Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15:555–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Düvel 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  PubMed Central  CAS  Google Scholar 

  • Eilers M, Eisenman RN (2008) Myc’s broad reach. Genes Dev 22:2755–2766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–3899

    Article  CAS  PubMed  Google Scholar 

  • Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562

    Article  CAS  PubMed  Google Scholar 

  • Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, Garcia-Echeverria C, Weissleder R, Mahmood U, Cantley LC, Wong KK (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Espenshade PJ, Hughes AL (2007) Regulation of sterol synthesis in eukaryotes. Annu Rev Genet 41:401–427

    Article  CAS  PubMed  Google Scholar 

  • Fan CD, Lum MA, Xu C, Black JD, Wang X (2013a) Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response. J Biol Chem 288:1674–1684

    Article  CAS  PubMed  Google Scholar 

  • Fan J, Kamphorst JJ, Mathew R, Chung MK, White E, Shlomi T, Rabinowitz JD (2013b) Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol Syst Biol 9:712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9:425–434

    Article  CAS  PubMed  Google Scholar 

  • Franke TF, Kaplan DR, Cantley LC, Toker A (1997) Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 275:665–668

    Article  CAS  PubMed  Google Scholar 

  • Fruman DA, Cantley LC (2014) Idelalisib–a PI3Kδ inhibitor for B-cell cancers. N Engl J Med 370:1061–1062

    Article  PubMed  PubMed Central  Google Scholar 

  • Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13:140–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gan B, Lim C, Chu G, Hua S, Ding Z, Collins M, Hu J, Jiang S, Fletcher-Sananikone E, Zhuang L, Chang M, Zheng H, Wang YA, Kwiatkowski DJ, Kaelin WGJ, Signoretti S, DePinho RA (2010) FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell 18:472–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ganapathy V, Thangaraju M, Prasad PD (2009) Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther 121:29–40

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  PubMed Central  Google Scholar 

  • García JM, Silva J, Peña C, Garcia V, Rodríguez R, Cruz MA, Cantos B, Provencio M, España P, Bonilla F (2004) Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosom Cancer 41:117–124

    Article  PubMed  CAS  Google Scholar 

  • Gebhardt R, Kleemann E (1987) Hormonal regulation of amino acid transport system N in primary cultures of rat hepatocytes. Eur J Biochem 166:339–344

    Article  CAS  PubMed  Google Scholar 

  • Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli MM, Boland CR (2004) Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res 64:3014–3021

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez E, McGraw TE (2009) Insulin-modulated Akt subcellular localization determines Akt isoform-specific signaling. Proc Natl Acad Sci USA 106:7004–7009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N (2001) Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15:1406–1418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, Jordan A, Beck AH, Sabatini DM (2014) A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov 4:554–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gregory MA, Qi Y, Hann SR (2003) Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J Biol Chem 278:51606–51612

    Article  CAS  PubMed  Google Scholar 

  • Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, Guarente L (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126:941–954

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  • Hensley CT, Wasti AT, DeBerardinis RJ (2013) Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest 123:3678–3684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang S, Czech MP (2007) The GLUT4 glucose transporter. Cell Metab 5:237–252

    Article  CAS  PubMed  Google Scholar 

  • Ikonomov OC, Sbrissa D, Dondapati R, Shisheva A (2007) ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes. Exp Cell Res 313:2404–2416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikonomov OC, Sbrissa D, Mlak K, Shisheva A (2002) Requirement for PIKfyve enzymatic activity in acute and long-term insulin cellular effects. Endocrinology 143:4742–4754

    Article  CAS  PubMed  Google Scholar 

  • Ikonomov OC, Sbrissa D, Shisheva A (2009) YM201636, an inhibitor of retroviral budding and PIKfyve-catalyzed PtdIns(3,5)P2 synthesis, halts glucose entry by insulin in adipocytes. Biochem Biophys Res Commun 382:566–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • John S, Weiss JN, Ribalet B (2011) Subcellular localization of hexokinases I and II directs the metabolic fate of glucose. PLoS ONE 6:e17674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP (1999) Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 64:1305–1315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmana J, Rajendran A, Papa A, Spencer K, Lyssiotis CA, Nardella C, Pandolfi PP, Baselga J, Scully R, Asara JM, Cantley LC, Wulf GM (2012) Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov 2:1048–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katome T, Obata T, Matsushima R, Masuyama N, Cantley LC, Gotoh Y, Kishi K, Shiota H, Ebina Y (2003) Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions. J Biol Chem 278:28312–28323

    Article  CAS  PubMed  Google Scholar 

  • Khatri S, Yepiskoposyan H, Gallo CA, Tandon P, Plas DR (2010) FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. J Biol Chem 285:15960–15965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185

    Article  PubMed  CAS  Google Scholar 

  • Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, Dang CV (2004a) Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 24:5923–5936

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim KH, Song MJ, Yoo EJ, Choe SS, Park SD, Kim JB (2004b) Regulatory role of glycogen synthase kinase 3 for transcriptional activity of ADD1/SREBP1c. J Biol Chem 279:51999–52006

    Article  CAS  PubMed  Google Scholar 

  • Kohn AD, Summers SA, Birnbaum MJ, Roth RA (1996) Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem 271:31372–31378

    Article  CAS  PubMed  Google Scholar 

  • Kotani K, Carozzi AJ, Sakaue H, Hara K, Robinson LJ, Clark SF, Yonezawa K, James DE, Kasuga M (1995) Requirement for phosphoinositide 3-kinase in insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes. Biochem Biophys Res Commun 209:343–348

    Article  CAS  PubMed  Google Scholar 

  • Kress TR, Cannell IG, Brenkman AB, Samans B, Gaestel M, Roepman P, Burgering BM, Bushell M, Rosenwald A, Eilers M (2011) The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Mol Cell 41:445–457

    Article  CAS  PubMed  Google Scholar 

  • 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 Cancer 17:101–106

    Article  CAS  PubMed  Google Scholar 

  • 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 Cancer 122:2422–2428

    Google Scholar 

  • 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  CAS  PubMed  PubMed Central  Google Scholar 

  • Larance M, Ramm G, Stockli J, van Dam EM, Winata S, Wasinger V, Simpson F, Graham M, Junutula JR, Guilhaus M, James DE (2005) Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. J Biol Chem 280:37803–37813

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  PubMed Central  Google Scholar 

  • Li B, Simon MC (2013) Molecular pathways: targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer. Clin Cancer Res 19:5835–5841

    Article  CAS  PubMed  Google Scholar 

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947

    Article  CAS  PubMed  Google Scholar 

  • Li R, Wei J, Jiang C, Liu D, Deng L, Zhang K, Wang P (2013) Akt SUMOylation regulates cell proliferation and tumorigenesis. Cancer Res 73:5742–5753

    Article  CAS  PubMed  Google Scholar 

  • Liu P, Begley M, Michowski W, Inuzuka H, Ginzberg M, Gao D, Tsou P, Gan W, Papa A, Kim BM, Wan L, Singh A, Zhai B, Yuan M, Wang Z, Gygi SP, Lee TH, Lu KP, Toker A, Pandolfi PP, Asara JM, Kirschner MW, Sicinski P, Cantley L, Wei W (2014) Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 508:541–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Low SY, Taylor PM, Rennie MJ (1996) Responses of glutamine transport in cultured rat skeletal muscle to osmotically induced changes in cell volume. J Physiol 492:877–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J, Liu JM, Yang DM, Yang WK, Shen CY (2000) PIK3CA as an oncogene in cervical cancer. Oncogene 19:2739–2744

    Article  CAS  PubMed  Google Scholar 

  • Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378

    Article  CAS  PubMed  Google Scholar 

  • Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, Hay N (2004a) Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 16:819–830

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malanga D, Scrima M, De Marco C, Fabiani F, De Rosa N, De Gisi S, Malara N, Savino R, Rocco G, Chiappetta G, Franco R, Tirino V, Pirozzi G, Viglietto G (2008) Activating E17 K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung. Cell Cycle 7:665–669

    Article  CAS  PubMed  Google Scholar 

  • Manning BD, Cantley LC (2003) United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem Soc Trans 31:573–578

    Article  CAS  PubMed  Google Scholar 

  • Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10:151–162

    Article  CAS  PubMed  Google Scholar 

  • Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T, Iwanami A, Liu F, Villa GR, Gu Y, Campos C, Zhu S, Yang H, Yong WH, Cloughesy TF, Mellinghoff IK, Cavenee WK, Shaw RJ, Mischel PS (2013) mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab 18:726–739

    Article  CAS  PubMed  Google Scholar 

  • Mathupala SP, Ko YH, Pedersen PL (2006) Hexokinase II: cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25:4777–4786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, Sanders ME, Yap JT, Van den Abbeele AD, Li Y, Cantley LC, Winer E, Arteaga CL (2014) Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 32:1202–1209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, Cantley LC, Manning BD (2014) Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156:771–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, Ushijima M, Mashima T, Seimiya H, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y (2008) ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res 68:8547–8554

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto S, Murphy AN, Brown JH (2008) Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ 15:521–529

    Article  CAS  PubMed  Google Scholar 

  • Moon JS, Jin WJ, Kwak JH, Kim HJ, Yun MJ, Kim JW, Park SW, Kim KS (2011) 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

    Article  CAS  PubMed  Google Scholar 

  • Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E (2007) Energy metabolism in tumor cells. FEBS J 274:1393–1418

    Article  CAS  PubMed  Google Scholar 

  • Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR (1999) Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 344(Pt 2):427–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Obata T, Yaffe MB, Leparc GG, Piro ET, Maegawa H, Kashiwagi A, Kikkawa R, Cantley LC (2000) Peptide and protein library screening defines optimal substrate motifs for AKT/PKB. J Biol Chem 275:36108–36115

    Article  CAS  PubMed  Google Scholar 

  • Obsil T, Ghirlando R, Anderson DE, Hickman AB, Dyda F (2003) Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. Biochemistry 42:15264–15272

    Article  CAS  PubMed  Google Scholar 

  • Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M (1994) Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem 269:3568–3573

    CAS  PubMed  Google Scholar 

  • Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275:21797–21800

    Article  CAS  PubMed  Google Scholar 

  • Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197

    Article  CAS  PubMed  Google Scholar 

  • Paradis S, Ruvkun G (1998) Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12:2488–2498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parikh H, Carlsson E, Chutkow WA, Johansson LE, Storgaard H, Poulsen P, Saxena R, Ladd C, Schulze PC, Mazzini MJ, Jensen CB, Krook A, Bjornholm M, Tornqvist H, Zierath JR, Ridderstrale M, Altshuler D, Lee RT, Vaag A, Groop LC, Mootha VK (2007) TXNIP regulates peripheral glucose metabolism in humans. PLoS Med 4:e158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L, Silliman N, Ptak J, Szabo S, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Lengauer C, Velculescu VE (2005) Colorectal cancer: mutations in a signalling pathway. Nature 436:792

    Article  CAS  PubMed  Google Scholar 

  • Pastorino JG, Hoek JB, Shulga N (2005) Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 65:10545–10554

    Article  CAS  PubMed  Google Scholar 

  • Pastorino JG, Shulga N, Hoek JB (2002) Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem 277:7610–7618

    Article  CAS  PubMed  Google Scholar 

  • Peck B, Ferber EC, Schulze A (2013) Antagonism between FOXO and MYC Regulates Cellular Powerhouse. Front Oncol 3:96

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  PubMed Central  Google Scholar 

  • Potapova IA, El-Maghrabi MR, Doronin SV, Benjamin WB (2000) Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 39:1169–1179

    Article  CAS  PubMed  Google Scholar 

  • Rácz A, Brass N, Heckel D, Pahl S, Remberger K, Meese E (1999) Expression analysis of genes at 3q26-q27 involved in frequent amplification in squamous cell lung carcinoma. Eur J Cancer 35:641–646

    Article  PubMed  Google Scholar 

  • Raivio KO, Lazar CS, Krumholz HR, Becker MA (1981) The phosphogluconate pathway and synthesis of 5-phosphoribosyl-1-pyrophosphate in human fibroblasts. Biochim Biophys Acta 678:51–57

    Article  CAS  PubMed  Google Scholar 

  • Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB (2003) Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol 23:7315–7328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Risso G, Pelisch F, Pozzi B, Mammi P, Blaustein M, Colman-Lerner A, Srebrow A (2013) Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle. Cell Cycle 12:3165–3174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roberts DJ, Tan-Sah VP, Smith JM, Miyamoto S (2013) Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J Biol Chem 288:23798–23806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robey RB, Hay N (2009) Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 19:25–31

    Article  CAS  PubMed  Google Scholar 

  • Robitaille AM, Christen S, Shimobayashi M, Cornu M, Fava LL, Moes S, Prescianotto-Baschong C, Sauer U, Jenoe P, Hall MN (2013) Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339:1320–1323

    Article  CAS  PubMed  Google Scholar 

  • Rodon J, Dienstmann R, Serra V, Tabernero J (2013) Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10:143–153

    Article  CAS  PubMed  Google Scholar 

  • Saci A, Cantley LC, Carpenter CL (2011) Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol Cell 42:50–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sale EM, Hodgkinson CP, Jones NP, Sale GJ (2006) A new strategy for studying protein kinase B and its three isoforms. Role of protein kinase B in phosphorylating glycogen synthase kinase-3, tuberin, WNK1, and ATP citrate lyase. Biochemistry 45:213–223

    Article  CAS  PubMed  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554

    Article  CAS  PubMed  Google Scholar 

  • Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, Garner CW, Lienhard GE (2003) Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 278:14599–14602

    Article  CAS  PubMed  Google Scholar 

  • Sasaki H, Okuda K, Kawano O, Yukiue H, Yano M, Fujii Y (2008) AKT1 and AKT2 mutations in lung cancer in a Japanese population. Mol Med Rep 1:663–666

    CAS  PubMed  Google Scholar 

  • Sbrissa D, Ikonomov OC, Strakova J, Shisheva A (2004) Role for a novel signaling intermediate, phosphatidylinositol 5-phosphate, in insulin-regulated F-actin stress fiber breakdown and GLUT4 translocation. Endocrinology 145:4853–4865

    Article  CAS  PubMed  Google Scholar 

  • Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT (2000) A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 60:3504–3513

    PubMed  Google Scholar 

  • Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:32529–32537

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, Dalla-Favera R, Dang CV (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci U S A 94:6658–6663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shisheva A (2008) PIKfyve: partners, significance, debates and paradoxes. Cell Biol Int 32:591–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shoji K, Oda K, Nakagawa S, Hosokawa S, Nagae G, Uehara Y, Sone K, Miyamoto Y, Hiraike H, Hiraike-Wada O, Nei T, Kawana K, Kuramoto H, Aburatani H, Yano T, Taketani Y (2009) The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas. Br J Cancer 101:145–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silhan J, Vacha P, Strnadova P, Vecer J, Herman P, Sulc M, Teisinger J, Obsilova V, Obsil T (2009) 14-3-3 protein masks the DNA binding interface of forkhead transcription factor FOXO4. J Biol Chem 284:19349–19360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496:101–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Staal SP (1987) Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci USA 84:5034–5037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stanton RC (2012) Glucose-6-phosphate dehydrogenase, NADPH, and cell survival. IUBMB Life 64:362–369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT (1998) Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279:710–714

    Article  CAS  PubMed  Google Scholar 

  • Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, Nik-Zainal S, Martin S, Varela I, Bignell GR, Yates LR, Papaemmanuil E, Beare D, Butler A, Cheverton A, Gamble J, Hinton J, Jia M, Jayakumar A, Jones D, Latimer C, Lau KW, McLaren S, McBride DJ, Menzies A, Mudie L, Raine K, Rad R, Chapman MS, Teague J, Easton D, Langerod A, Lee MT, Shen CY, Tee BT, Huimin BW, Broeks A, Vargas AC, Turashvili G, Martens J, Fatima A, Miron P, Chin SF, Thomas G, Boyault S, Mariani O, Lakhani SR, van de Vijver M, van ‘t Veer L, Foekens J, Desmedt C, Sotiriou C, Tutt A, Caldas C, Reis-Filho JS, Aparicio SA, Salomon AV, Borresen-Dale AL, Richardson AL, Campbell PJ, Futreal PA, Stratton MR (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404

    Google Scholar 

  • Stoltzman CA, Peterson CW, Breen KT, Muoio DM, Billin AN, Ayer DE (2008) Glucose sensing by MondoA: Mlx complexes: a role for hexokinases and direct regulation of thioredoxin-interacting protein expression. Proc Natl Acad Sci USA 105:6912–6917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Storz P, Toker A (2002) 3’-phosphoinositide-dependent kinase-1 (PDK-1) in PI 3-kinase signaling. Front Biosci 7:d886–d902

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Huang J, Homma T, Kita D, Klocker H, Schafer G, Boyle P, Ohgaki H (2009) Genetic alterations in the PI3 K pathway in prostate cancer. Anticancer Res 29:1739–1743

    CAS  PubMed  Google Scholar 

  • Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyanchuk V, Jin J, Harper JW, Ericsson J (2005) Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7). Cell Metab 1:379–391

    Article  CAS  PubMed  Google Scholar 

  • Tadros LB, Taylor PM, Rennie MJ (1993) Characteristics of glutamine transport in primary tissue culture of rat skeletal muscle. Am J Physiol 265:E135–E144

    CAS  PubMed  Google Scholar 

  • Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J (2002) Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA 99:13571–13576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13:1259–1268

    Article  CAS  PubMed  Google Scholar 

  • Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J, Sawyers CL (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12:122–127

    Article  CAS  PubMed  Google Scholar 

  • Toker A (2012) Phosphoinositide 3-kinases-a historical perspective. Subcell Biochem 58:95–110

    Article  CAS  PubMed  Google Scholar 

  • Toker A, Cantley LC (1997) Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387:673–676

    Article  CAS  PubMed  Google Scholar 

  • Tzivion G, Dobson M, Ramakrishnan G (2011) FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta 1813:1938–1945

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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  CAS  Google Scholar 

  • van der Vos KE, Eliasson P, Proikas-Cezanne T, Vervoort SJ, van Boxtel R, Putker M, van Zutphen IJ, Mauthe M, Zellmer S, Pals C, Verhagen LP, Groot Koerkamp MJ, Braat AK, Dansen TB, Holstege FC, Gebhardt R, Burgering BM, Coffer PJ (2012) Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy. Nat Cell Biol 14:829–837

    Article  PubMed  CAS  Google Scholar 

  • Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9:316–323

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vanhaesebroeck B, Waterfield MD (1999) Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res 253:239–254

    Article  CAS  PubMed  Google Scholar 

  • Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Fridman A, Blackledge W, Connelly S, Wilson IA, Pilz RB, Boss GR (2009) The phosphatidylinositol 3-kinase/akt cassette regulates purine nucleotide synthesis. J Biol Chem 284:3521–3528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wasa M, Wang HS, Tazuke Y, Okada A (2001) Insulin-like growth factor-I stimulates amino acid transport in a glutamine-deprived human neuroblastoma cell line. Biochim Biophys Acta 1525:118–124

    Article  CAS  PubMed  Google Scholar 

  • Weinhouse S (1976) The Warburg hypothesis fifty years later. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 87:115–126

    Article  CAS  PubMed  Google Scholar 

  • Welcker M, Orian A, Jin J, Grim JE, Harper JW, Eisenman RN, Clurman BE (2004) The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA 101:9085–9090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Whitman M, Downes CP, Keeler M, Keller T, Cantley L (1988) Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 332:644–646

    Article  CAS  PubMed  Google Scholar 

  • Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM (1985) Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315:239–242

    Article  CAS  PubMed  Google Scholar 

  • Wieman HL, Wofford JA, Rathmell JC (2007) Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell 18:1437–1446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N, Cairns R, Hawkins C, Guha A (2011) Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med 208:313–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, Shen CH, Wen J, Asara J, McGraw TE, Kahn BB, Cantley LC (2013) AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell 49:1167–1175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang WL, Jin G, Li CF, Jeong YS, Moten A, Xu D, Feng Z, Chen W, Cai Z, Darnay B, Gu W, Lin HK (2013) Cycles of ubiquitination and deubiquitination critically regulate growth factor-mediated activation of Akt signaling. Sci Signal 6:ra3

    Google Scholar 

  • Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B, Hur L, Grabiner BC, Lin X, Darnay BG, Lin HK (2009b) The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325:1134–1138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang WL, Wu CY, Wu J, Lin HK (2010) Regulation of Akt signaling activation by ubiquitination. Cell Cycle 9:487–497

    PubMed  PubMed Central  Google Scholar 

  • Yeo H, Lyssiotis CA, Zhang Y, Ying H, Asara JM, Cantley LC, Paik JH (2013) FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells. EMBO J 32:2589–2602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik JH, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, DePinho RA (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149:656–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Patil S, Chauhan B, Guo S, Powell DR, Le J, Klotsas A, Matika R, Xiao X, Franks R, Heidenreich KA, Sajan MP, Farese RV, Stolz DB, Tso P, Koo SH, Montminy M, Unterman TG (2006) FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem 281:10105–10117

    Article  CAS  PubMed  Google Scholar 

  • Zhao JJ, Gjoerup OV, Subramanian RR, Cheng Y, Chen W, Roberts TM, Hahn WC (2003) Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase. Cancer Cell 3:483–495

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Zhou QL, Jiang ZY, Holik J, Chawla A, Hagan GN, Leszyk J, Czech MP (2008) Akt substrate TBC1D1 regulates GLUT1 expression through the mTOR pathway in 3T3-L1 adipocytes. Biochem J 411:647–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu J, Blenis J, Yuan J (2008) Activation of PI3 K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc Natl Acad Sci USA 105:6584–6589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14:391–396

    CAS  PubMed  PubMed Central  Google Scholar 

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Lien, E.C., Lyssiotis, C.A., Cantley, L.C. (2016). Metabolic Reprogramming by the PI3K-Akt-mTOR Pathway in Cancer. In: Cramer, T., A. Schmitt, C. (eds) Metabolism in Cancer. Recent Results in Cancer Research, vol 207. Springer, Cham. https://doi.org/10.1007/978-3-319-42118-6_3

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