89
Views
109
CrossRef citations to date
0
Altmetric
Minireview

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

REFERENCES

  • Nusse R, Varmus HE. 1982. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31:99–109.
  • Kanazawa A, Tsukada S, Sekine A, Tsunoda T, Takahashi A, Kashiwagi A, Tanaka Y, Babazono T, Matsuda M, Kaku K, Iwamoto Y, Kawamori R, Kikkawa R, Nakamura Y, Maeda S. 2004. Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes. Am J Hum Genet 75:832–843. http://dx.doi.org/10.1086/425340.
  • Guo YF, Xiong DH, Shen H, Zhao LJ, Xiao P, Guo Y, Wang W, Yang TL, Recker RR, Deng HW. 2006. Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study. J Med Genet 43:798–803. http://dx.doi.org/10.1136/jmg.2006.041715.
  • Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K. 2006. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323. http://dx.doi.org/10.1038/ng1732.
  • Mani A, Radhakrishnan J, Wang H, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP. 2007. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278–1282. http://dx.doi.org/10.1126/science.1136370.
  • Behari J, Li H, Liu S, Stefanovic-Racic M, Alonso L, O'Donnell CP, Shiva S, Singamsetty S, Watanabe Y, Singh VP, Liu Q. 2014. β-Catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice. Am J Pathol pii:S0002-9440(14)00509-4. http://dx.doi.org/10.1016/j.ajpath.2014.08.022.
  • Elghazi L, Gould AP, Weiss AJ, Barker DJ, Callaghan J, Opland D, Myers M, Cras-Meneur C, Bernal-Mizrachi E. 2012. Importance of β-catenin in glucose and energy homeostasis. Sci Rep 2:693. http://dx.doi.org/10.1038/srep00693.
  • Mori H, Prestwich TC, Reid MA, Longo KA, Gerin I, Cawthorn WP, Susulic VS, Krishnan V, Greenfield A, Macdougald OA. 2012. Secreted frizzled-related protein 5 suppresses adipocyte mitochondrial metabolism through WNT inhibition. J Clin Invest 122:2405–2416. http://dx.doi.org/10.1172/JCI63604.
  • Zeve D, Seo J, Suh JM, Stenesen D, Tang W, Berglund ED, Wan Y, Williams LJ, Lim A, Martinez MJ, McKay RM, Millay DP, Olson EN, Graff JM. 2012. Wnt signaling activation in adipose progenitors promotes insulin-independent muscle glucose uptake. Cell Metab 15:492–504. http://dx.doi.org/10.1016/j.cmet.2012.03.010.
  • Ehrlund A, Mejhert N, Lorente-Cebrian S, Astrom G, Dahlman I, Laurencikiene J, Ryden M. 2013. Characterization of the Wnt inhibitors secreted frizzled-related proteins (SFRPs) in human adipose tissue. J Clin Endocrinol Metab 98:E503–8. http://dx.doi.org/10.1210/jc.2012-3416.
  • Gauger KJ, Bassa LM, Henchey EM, Wyman J, Bentley B, Brown M, Shimono A, Schneider SS. 2013. Mice deficient in sfrp1 exhibit increased adiposity, dysregulated glucose metabolism, and enhanced macrophage infiltration. PLoS One 8:e78320. http://dx.doi.org/10.1371/journal.pone.0078320.
  • Lee SY, Jeon HM, Ju MK, Kim CH, Yoon G, Han SI, Park HG, Kang HS. 2012. Wnt/Snail signaling regulates cytochrome C oxidase and glucose metabolism. Cancer Res 72:3607–3617. http://dx.doi.org/10.1158/0008-5472.CAN-12-0006.
  • Sherwood V, Chaurasiya SK, Ekstrom EJ, Guilmain W, Liu Q, Koeck T, Brown K, Hansson K, Agnarsdottir M, Bergqvist M, Jirstrom K, Ponten F, James P, Andersson T. 2013. WNT5A-mediated β-catenin-independent signalling is a novel regulator of cancer cell metabolism. 35:784–794. Carcinogenesis http://dx.doi.org/10.1093/carcin/bgt390.
  • Pate KT, Stringari C, Sprowl-Tanio S, Wang K, TeSlaa T, Hoverter NP, McQuade MM, Garner C, Digman MA, Teitell MA, Edwards RA, Gratton E, Waterman ML. 2014. Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J 33:1454–1473. http://dx.doi.org/10.15252/embj.201488598.
  • Yang L, Perez AA, Fujie S, Warden C, Li J, Wang Y, Yung B, Chen YR, Liu X, Zhang H, Zheng S, Liu Z, Ann D, Yen Y. 2014. Wnt modulates MCL1 to control cell survival in triple negative breast cancer. BMC Cancer 14:124. http://dx.doi.org/10.1186/1471-2407-14-124.
  • Clevers H, Nusse R. 2012. Wnt/β-catenin signaling and disease. Cell 149:1192–1205. http://dx.doi.org/10.1016/j.cell.2012.05.012.
  • Clevers H. 2006. Wnt/β-catenin signaling in development and disease. Cell 127:469–480. http://dx.doi.org/10.1016/j.cell.2006.10.018.
  • Valenta T, Hausmann G, Basler K. 2012. The many faces and functions of β-catenin. EMBO J 31:2714–2736. http://dx.doi.org/10.1038/emboj.2012.150.
  • Kawano Y, Kypta R. 2003. Secreted antagonists of the Wnt signalling pathway. J Cell Sci 116:2627–2634. http://dx.doi.org/10.1242/jcs.00623.
  • Fearon ER, Vogelstein B. 1990. A genetic model for colorectal tumorigenesis. Cell 61:759–767.
  • Stewart DJ. 1 July 2014. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst 106:djt356. http://dx.doi.org/10.1093/jnci/djt356.
  • Laurent-Puig P, Zucman-Rossi J. 2006. Genetics of hepatocellular tumors. Oncogene 25:3778–3786. http://dx.doi.org/10.1038/sj.onc.1209547.
  • Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. 2000. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 24:245–250. http://dx.doi.org/10.1038/73448.
  • Zurawel RH, Chiappa SA, Allen C, Raffel C. 1998. Sporadic medulloblastomas contain oncogenic β-catenin mutations. Cancer Res 58:896–899.
  • Palacios J, Gamallo C. 1998. Mutations in the β-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res 58:1344–1347.
  • Bao R, Christova T, Song S, Angers S, Yan X, Attisano L. 2012. Inhibition of tankyrases induces axin stabilization and blocks Wnt signalling in breast cancer cells. PLoS One 7:e48670. http://dx.doi.org/10.1371/journal.pone.0048670.
  • Anastas JN, Moon RT. 2013. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13:11–26. http://dx.doi.org/10.1038/nrc3419.
  • Chien AJ, Moore EC, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ, Major MB, Hwang ST, Rimm DL, Moon RT. 2009. Activated Wnt/β-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proc Natl Acad Sci U S A 106:1193–1198. http://dx.doi.org/10.1073/pnas.0811902106.
  • Horvath LG, Henshall SM, Lee CS, Kench JG, Golovsky D, Brenner PC, O'Neill GF, Kooner R, Stricker PD, Grygiel JJ, Sutherland RL. 2005. Lower levels of nuclear β-catenin predict for a poorer prognosis in localized prostate cancer. Int J Cancer 113:415–422. http://dx.doi.org/10.1002/ijc.20599.
  • Dejmek J, Safholm A, Kamp Nielsen C, Andersson T, Leandersson K. 2006. Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1alpha signaling in human mammary epithelial cells. Mol Cell Biol 26:6024–6036. http://dx.doi.org/10.1128/MCB.02354-05.
  • Sheldahl LC, Park M, Malbon CC, Moon RT. 1999. Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Curr Biol 9:695–698.
  • Kuhl M, Sheldahl LC, Malbon CC, Moon RT. 2000. Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. J Biol Chem 275:12701–12711. http://dx.doi.org/10.1074/jbc.275.17.12701.
  • Choi SC, Han JK. 2002. Xenopus Cdc42 regulates convergent extension movements during gastrulation through Wnt/Ca2+ signaling pathway. Dev Biol 244:342–357. http://dx.doi.org/10.1006/dbio.2002.0602.
  • Huang T, Xie Z, Wang J, Li M, Jing N, Li L. 2011. Nuclear factor of activated T cells (NFAT) proteins repress canonical Wnt signaling via its interaction with Dishevelled (Dvl) protein and participate in regulating neural progenitor cell proliferation and differentiation. J Biol Chem 286:37399–37405. http://dx.doi.org/10.1074/jbc.M111.251165.
  • Saneyoshi T, Kume S, Amasaki Y, Mikoshiba K. 2002. The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos. Nature 417:295–299. http://dx.doi.org/10.1038/417295a.
  • Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Matsumoto K. 2003. The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/β-catenin signaling. Mol Cell Biol 23:131–139. http://dx.doi.org/10.1128/MCB.23.1.131-139.2003.
  • Wallingford JB. 2012. Planar cell polarity and the developmental control of cell behavior in vertebrate embryos. Annu Rev Cell Dev Biol 28:627–653. http://dx.doi.org/10.1146/annurev-cellbio-092910-154208.
  • Ybot-Gonzalez P, Savery D, Gerrelli D, Signore M, Mitchell CE, Faux CH, Greene ND, Copp AJ. 2007. Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure. Development 134:789–799. http://dx.doi.org/10.1242/dev.000380.
  • Lejeune S, Huguet EL, Hamby A, Poulsom R, Harris AL. 1995. Wnt5a cloning, expression, and up-regulation in human primary breast cancers. Clin Cancer Res 1:215–222.
  • Dejmek J, Dejmek A, Safholm A, Sjolander A, Andersson T. 2005. Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis. Cancer Res 65:9142–9146. http://dx.doi.org/10.1158/0008-5472.CAN-05-1710.
  • Da Forno PD, Pringle JH, Hutchinson P, Osborn J, Huang Q, Potter L, Hancox RA, Fletcher A, Saldanha GS. 2008. WNT5A expression increases during melanoma progression and correlates with outcome. Clin Cancer Res 14:5825–5832. http://dx.doi.org/10.1158/1078-0432.CCR-07-5104.
  • Kurayoshi M, Oue N, Yamamoto H, Kishida M, Inoue A, Asahara T, Yasui W, Kikuchi A. 2006. Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Res 66:10439–10448. http://dx.doi.org/10.1158/0008-5472.CAN-06-2359.
  • Kestler HA, Kuhl M. 2008. From individual Wnt pathways towards a Wnt signalling network. Philos Trans R Soc Lond B Biol Sci 363:1333–1347. http://dx.doi.org/10.1098/rstb.2007.2251.
  • van Amerongen R, Nusse R. 2009. Towards an integrated view of Wnt signaling in development. Development 136:3205–3214. http://dx.doi.org/10.1242/dev.033910.
  • Metallo CM, Vander Heiden MG. 2013. Understanding metabolic regulation and its influence on cell physiology. Mol Cell 49:388–398. http://dx.doi.org/10.1016/j.molcel.2013.01.018.
  • Sethi JK, Vidal-Puig A. 2010. Wnt signalling and the control of cellular metabolism. Biochem J 427:1–17. http://dx.doi.org/10.1042/BJ20091866.
  • Yoon JC, Ng A, Kim BH, Bianco A, Xavier RJ, Elledge SJ. 2010. Wnt signaling regulates mitochondrial physiology and insulin sensitivity. Genes Dev 24:1507–1518. http://dx.doi.org/10.1101/gad.1924910.
  • Esen E, Chen J, Karner CM, Okunade AL, Patterson BW, Long F. 2013. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab 17:745–755. http://dx.doi.org/10.1016/j.cmet.2013.03.017.
  • Warburg O. 1956. On the origin of cancer cells. Science 123:309–314.
  • Vander Heiden MG, Cantley LC, Thompson CB. 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033. http://dx.doi.org/10.1126/science.1160809.
  • 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 U S A 104:19345–19350. http://dx.doi.org/10.1073/pnas.0709747104.
  • 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 U S A 105:18782–18787. http://dx.doi.org/10.1073/pnas.0810199105.
  • 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. http://dx.doi.org/10.1038/nature07823.
  • Menendez JA, Lupu R. 2007. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7:763–777. http://dx.doi.org/10.1038/nrc2222.
  • Schwartz DR, Wu R, Kardia SL, Levin AM, Huang CC, Shedden KA, Kuick R, Misek DE, Hanash SM, Taylor JM, Reed H, Hendrix N, Zhai Y, Fearon ER, Cho KR. 2003. Novel candidate targets of beta-catenin/T-cell factor signaling identified by gene expression profiling of ovarian endometrioid adenocarcinomas. Cancer Res 63:2913–2922.
  • Zhang X, Gaspard JP, Chung DC. 2001. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res 61:6050–6054.
  • Qu B, Liu BR, Du YJ, Chen J, Cheng YQ, Xu W, Wang XH. 2014. Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncol Lett 7:1175–1178. http://dx.doi.org/10.3892/ol.2014.1828.
  • Liu Z, Sun B, Qi L, Li Y, Zhao X, Zhang D, Zhang Y. 10 June 2014. Dickkopf-1 expression is downregulated along colorectal adenoma-carcinoma sequence and correlates with reduced microvessel density and VEGF expression. Histopathology http://dx.doi.org/10.1111/his.12474.
  • Rudolph B, Saffrich R, Zwicker J, Henglein B, Muller R, Ansorge W, Eilers M. 1996. Activation of cyclin-dependent kinases by Myc mediates induction of cyclin A, but not apoptosis. EMBO J 15:3065–3076.
  • Leone G, DeGregori J, Sears R, Jakoi L, Nevins JR. 1997. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature 387:422–426. http://dx.doi.org/10.1038/387422a0.
  • Galaktionov K, Chen X, Beach D. 1996. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 382:511–517. http://dx.doi.org/10.1038/382511a0.
  • Daksis JI, Lu RY, Facchini LM, Marhin WW, Penn LJ. 1994. Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene 9:3635–3645.
  • 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. http://dx.doi.org/10.1016/j.ccr.2007.07.006.
  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW. 1998. Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512.
  • van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H. 2002. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111:241–250. http://dx.doi.org/10.1016/S0092-8674(02)01014-0.
  • Sansom OJ, Meniel VS, Muncan V, Phesse TJ, Wilkins JA, Reed KR, Vass JK, Athineos D, Clevers H, Clarke AR. 2007. Myc deletion rescues Apc deficiency in the small intestine. Nature 446:676–679. http://dx.doi.org/10.1038/nature05674.
  • Cowling VH, D'Cruz CM, Chodosh LA, Cole MD. 2007. c-Myc transforms human mammary epithelial cells through repression of the Wnt inhibitors DKK1 and SFRP1. Mol Cell Biol 27:5135–5146. http://dx.doi.org/10.1128/MCB.02282-06.
  • Dang CV. 2013. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb Perspect Med 3:a014217. http://dx.doi.org/10.1101/cshperspect.a014217.
  • Dang CV, Le A, Gao P. 2009. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res 15:6479–6483. http://dx.doi.org/10.1158/1078-0432.CCR-09-0889.
  • Yang WW, Zheng YH, Xia Y, Ji HT, Chen XM, Guo F, Lyssiotis CA, Aldape K, Cantley LC, Liu ZM. 2012. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 14:1295–1304. http://dx.doi.org/10.1038/Ncb2629.
  • Wu H, Li Z, Yang P, Zhang L, Fan Y, Li Z. 2014. PKM2 depletion induces the compensation of glutaminolysis through β-catenin/c-Myc pathway in tumor cells. Cell Signal 26:2397–2405. http://dx.doi.org/10.1016/j.cellsig.2014.07.024.
  • Thompson CB. 2014. Wnt meets Warburg: another piece in the puzzle? EMBO J 33:1420–1422. http://dx.doi.org/10.15252/embj.201488785.
  • Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, Gao X, Aldape K, Lu Z. 2011. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature 480:118–122. http://dx.doi.org/10.1038/nature10598.
  • Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. 2011. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145:732–744. http://dx.doi.org/10.1016/j.cell.2011.03.054.
  • Yu Z, Huang L, Zhang T, Yang F, Xie L, Liu J, Song S, Miao P, Zhao L, Zhao X, Huang G. 2013. PIM2 phosphorylates PKM2 and promotes glycolysis in cancer cells. J Biol Chem 288:35406–35416. http://dx.doi.org/10.1074/jbc.M113.508226.
  • Liu J, Gao L, Zhang H, Wang D, Wang M, Zhu J, Pang C, Wang C. 2013. Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase kinase 3β–β-catenin-mediated lung cancer metastasis. J Biol Chem 288:29965–29973. http://dx.doi.org/10.1074/jbc.M113.450106.
  • Murphy MP. 2009. How mitochondria produce reactive oxygen species. Biochem J 417:1–13. http://dx.doi.org/10.1042/BJ20081386.
  • Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, Lin Y, Yao J, Shi J, Kang T, Lorkiewicz P, St Clair D, Hung MC, Evers BM, Zhou BP. 2013. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 23:316–331. http://dx.doi.org/10.1016/j.ccr.2013.01.022.
  • Funato Y, Michiue T, Asashima M, Miki H. 2006. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-β-catenin signalling through dishevelled. Nat Cell Biol 8:501–508. http://dx.doi.org/10.1038/ncb1405.
  • Chocarro-Calvo A, Garcia-Martinez JM, Ardila-Gonzalez S, De la Vieja A, Garcia-Jimenez C. 2013. Glucose-induced β-catenin acetylation enhances Wnt signaling in cancer. Mol Cell 49:474–486. http://dx.doi.org/10.1016/j.molcel.2012.11.022.
  • Winder WW, Hardie DG. 1999. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol 277:E1–10.
  • Kwan HT, Chan DW, Cai PC, Mak CS, Yung MM, Leung TH, Wong OG, Cheung AN, Ngan HY. 2013. AMPK activators suppress cervical cancer cell growth through inhibition of DVL3 mediated Wnt/β-catenin signaling activity. PLoS One 8:e53597. http://dx.doi.org/10.1371/journal.pone.0053597.
  • Zoncu R, Efeyan A, Sabatini DM. 2011. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35. http://dx.doi.org/10.1038/nrm3025.
  • Sengupta S, Peterson TR, Sabatini DM. 2010. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 40:310–322. http://dx.doi.org/10.1016/j.molcel.2010.09.026.
  • Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL. 2006. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126:955–968. http://dx.doi.org/10.1016/j.cell.2006.06.055.
  • Tahir SA, Yang G, Goltsov A, Song KD, Ren C, Wang J, Chang W, Thompson TC. 2013. Caveolin-1-LRP6 signaling module stimulates aerobic glycolysis in prostate cancer. Cancer Res 73:1900–1911. http://dx.doi.org/10.1158/0008-5472.CAN-12-3040.
  • Kim MS, Chang X, LeBron C, Nagpal JK, Lee J, Huang Y, Yamashita K, Trink B, Ratovitski EA, Sidransky D. 2010. Neurofilament heavy polypeptide regulates the Akt–β-catenin pathway in human esophageal squamous cell carcinoma. PLoS One 5:e9003. http://dx.doi.org/10.1371/journal.pone.0009003.
  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. 1995. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789. http://dx.doi.org/10.1038/378785a0.
  • Tredan O, Galmarini CM, Patel K, Tannock IF. 2007. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454. http://dx.doi.org/10.1093/jnci/djm135.
  • Cantor JR, Sabatini DM. 2012. Cancer cell metabolism: one hallmark, many faces. Cancer Discov 2:881–898. http://dx.doi.org/10.1158/2159-8290.CD-12-0345.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.