Skip to main content
SpringerLink
Log in
Book cover

Insulin Resistance and Cancer pp 193–211Cite as

AMP-Activated Protein Kinase and Cancer Cell Metabolism

  • Chapter
  • First Online:

  • 713 Accesses

Part of the book series: Energy Balance and Cancer ((EBAC,volume 1))

Abstract

AMP-activated protein kinase (AMPK) is an essential energy sensor that exerts its effect at both the cellular and organismal levels. In response to increases in the AMP to ATP ratio, typically under energy stress conditions, AMPK phosphorylates downstream regulatory proteins and enzymatic effectors to upregulate ATP-producing catabolic pathways and downregulate ATP-consuming processes. The identification of the tumor suppressor LKB1 as a primary upstream activating kinase of AMPK has prompted intense inquiry into its possible role in cancer. Indeed, preclinical studies suggest that AMPK is a promising target for cancer therapeutics. More interestingly, drugs that activate AMPK, such as metformin, have been widely used for treating type 2 diabetes, and could therefore be quickly adapted for cancer treatment. In this chapter, we will discuss the structure and regulation of AMPK, its role in controlling cell growth, and proliferation and the therapeutic implications of these findings on cancer prevention and treatment.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13:472–482

    Article  CAS  PubMed  Google Scholar 

  2. Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823–837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20

    Article  CAS  PubMed  Google Scholar 

  6. Hsu PP, Sabatini DM (2008) Cancer cell metabolism: warburg and beyond. Cell 134:703–707

    Article  CAS  PubMed  Google Scholar 

  7. Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8:774–785

    Article  CAS  PubMed  Google Scholar 

  8. McBride A, Ghilagaber S, Nikolaev A, Hardie DG (2009) The glycogen-binding domain on the AMPK beta subunit allows the kinase to act as a glycogen sensor. Cell Metab 9:23–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, Walker PA, Haire L, Eccleston JF, Davis CT, Martin SR, Carling D, Gamblin SJ (2007) Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449:496–500

    Article  CAS  PubMed  Google Scholar 

  10. Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D (2007) Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 403:139–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Steinberg GR, Michell BJ, van Denderen BJ, Watt MJ, Carey AL, Fam BC, Andrikopoulos S, Proietto J, Gorgun CZ, Carling D, Hotamisligil GS, Febbraio MA, Kay TW, Kemp BE (2006) Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab 4:465–474

    Article  CAS  PubMed  Google Scholar 

  12. Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25

    Article  CAS  PubMed  Google Scholar 

  13. Guigas B, Sakamoto K, Taleux N, Reyna SM, Musi N, Viollet B, Hue L (2009) Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators. IUBMB Life 61:18–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hardie DG (2007) AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 47:185–210

    Article  CAS  PubMed  Google Scholar 

  15. Zhou G, Sebhat IK, Zhang BB (2009) AMPK activators – potential therapeutics for metabolic and other diseases. Acta Physiol (Oxf) 196(1):175–190

    Article  CAS  Google Scholar 

  16. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hudson ER, Pan DA, James J, Lucocq JM, Hawley SA, Green KA, Baba O, Terashima T, Hardie DG (2003) A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr Biol 13:861–866

    Article  CAS  PubMed  Google Scholar 

  18. Polekhina G, Gupta A, Michell BJ, van Denderen B, Murthy S, Feil SC, Jennings IG, Campbell DJ, Witters LA, Parker MW, Kemp BE, Stapleton D (2003) AMPK beta subunit targets metabolic stress sensing to glycogen. Curr Biol 13:867–871

    Article  CAS  PubMed  Google Scholar 

  19. Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, Zhao G, Marsh K, Kym P, Jung P, Camp HS, Frevert E (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3:403–416

    Article  CAS  PubMed  Google Scholar 

  20. Pang T, Zhang ZS, Gu M, Qiu BY, Yu LF, Cao PR, Shao W, Su MB, Li JY, Nan FJ, Li J (2008) Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells. J Biol Chem 283:16051–16060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ellingson WJ, Chesser DG, Winder WW (2007) Effects of 3-phosphoglycerate and other metabolites on the activation of AMP-activated protein kinase by LKB1-STRAD-MO25. Am J Physiol Endocrinol Metab 292:E400–E407

    Article  CAS  PubMed  Google Scholar 

  22. Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, Lan F, Walsh K, Wierzbicki M, Verbeuren TJ, Cohen RA, Zang M (2008) SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 283:20015–20026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lan F, Cacicedo JM, Ruderman N, Ido Y (2008) SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 283:27628–27635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alessi DR, Sakamoto K, Bayascas JR (2006) LKB1-dependent signaling pathways. Annu Rev Biochem 75:137–163

    Article  CAS  PubMed  Google Scholar 

  25. Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Makela TP (2007) The LKB1 tumor suppressor kinase in human disease. Biochim Biophys Acta 1775:63–75

    CAS  PubMed  Google Scholar 

  26. Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, Westra WH, Herman JG, Sidransky D (2002) Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 62:3659–3662

    CAS  PubMed  Google Scholar 

  27. Hezel AF, Bardeesy N (2008) LKB1; linking cell structure and tumor suppression. Oncogene 27:6908–6919

    Article  CAS  PubMed  Google Scholar 

  28. Bardeesy N, Sinha M, Hezel AF, Signoretti S, Hathaway NA, Sharpless NE, Loda M, Carrasco DR, DePinho RA (2002) Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419:162–167

    Article  CAS  PubMed  Google Scholar 

  29. Jishage K, Nezu J, Kawase Y, Iwata T, Watanabe M, Miyoshi A, Ose A, Habu K, Kake T, Kamada N, Ueda O, Kinoshita M, Jenne DE, Shimane M, Suzuki H (2002) Role of Lkb1, the causative gene of Peutz-Jegher’s syndrome, in embryogenesis and polyposis. Proc Natl Acad Sci U S A 99:8903–8908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ylikorkala A, Rossi DJ, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M, Makela TP (2001) Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science 293:1323–1326

    Article  CAS  PubMed  Google Scholar 

  31. Dorfman J, Macara IG (2008) STRADalpha regulates LKB1 localization by blocking access to importin-alpha, and by association with Crm1 and exportin-7. Mol Biol Cell 19:1614–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG (2003) Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2:28

    Article  PubMed  PubMed Central  Google Scholar 

  33. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 101:3329–3335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13:2004–2008

    Article  CAS  PubMed  Google Scholar 

  35. Lizcano JM, Goransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Makela TP, Hardie DG, Alessi DR (2004) LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 23:833–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Boudeau J, Sapkota G, Alessi DR (2003) LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Lett 546:159–165

    Article  CAS  PubMed  Google Scholar 

  37. Tiainen M, Vaahtomeri K, Ylikorkala A, Makela TP (2002) Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1). Hum Mol Genet 11:1497–1504

    Article  CAS  PubMed  Google Scholar 

  38. Tiainen M, Ylikorkala A, Makela TP (1999) Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest. Proc Natl Acad Sci U S A 96:9248–9251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ, Clevers HC (2004) Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116:457–466

    Article  CAS  PubMed  Google Scholar 

  40. Martin SG, St Johnston D (2003) A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature 421:379–384

    Article  CAS  PubMed  Google Scholar 

  41. Watts JL, Morton DG, Bestman J, Kemphues KJ (2000) The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry. Development 127:1467–1475

    Article  CAS  PubMed  Google Scholar 

  42. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D (2005) Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2:21–33

    Article  CAS  PubMed  Google Scholar 

  43. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9–19

    Article  CAS  PubMed  Google Scholar 

  44. Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA (2005) The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem 280:29060–29066

    Article  CAS  PubMed  Google Scholar 

  45. Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, Witters LA, Kemp BE, Means AR (2008) Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab 7:377–388

    Article  CAS  PubMed  Google Scholar 

  46. Witczak CA, Sharoff CG, Goodyear LJ (2008) AMP-activated protein kinase in skeletal muscle: from structure and localization to its role as a master regulator of cellular metabolism. Cell Mol Life Sci 65:3737–3755

    Article  CAS  PubMed  Google Scholar 

  47. Momcilovic M, Hong SP, Carlson M (2006) Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem 281:25336–25343

    Article  CAS  PubMed  Google Scholar 

  48. Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C, Fumarola C, Farkas T, Lopez-Rivas A, Jaattela M (2009) TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J 28:677–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Xie M, Zhang D, Dyck JR, Li Y, Zhang H, Morishima M, Mann DL, Taffet GE, Baldini A, Khoury DS, Schneider MD (2006) A pivotal role for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc Natl Acad Sci U S A 103:17378–17383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22

    Article  CAS  PubMed  Google Scholar 

  51. Jacinto E, Lorberg A (2008) TOR regulation of AGC kinases in yeast and mammals. Biochem J 410:19–37

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18:1533–1538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  56. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283–293

    Article  CAS  PubMed  Google Scholar 

  57. Budanov AV, Karin M (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:451–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Drakos E, Atsaves V, Li J, Leventaki V, Andreeff M, Medeiros LJ, Rassidakis GZ (2009) Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma. Leukemia 23(4):754–790

    Article  CAS  Google Scholar 

  59. Rattan R, Giri S, Singh AK, Singh I (2005) 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J Biol Chem 280:39582–39593

    Article  CAS  PubMed  Google Scholar 

  60. Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB (2007) The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9:218–224

    Article  CAS  PubMed  Google Scholar 

  61. Short JD, Houston KD, Dere R, Cai SL, Kim J, Johnson CL, Broaddus RR, Shen J, Miyamoto S, Tamanoi F, Kwiatkowski D, Mills GB, Walker CL (2008) AMP-activated protein kinase signaling results in cytoplasmic sequestration of p27. Cancer Res 68:6496–6506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lee M, Vasioukhin V (2008) Cell polarity and cancer–cell and tissue polarity as a non-canonical tumor suppressor. J Cell Sci 121:1141–1150

    Article  CAS  PubMed  Google Scholar 

  63. Baas AF, Smit L, Clevers H (2004) LKB1 tumor suppressor protein: PARtaker in cell polarity. Trends Cell Biol 14:312–319

    Article  CAS  PubMed  Google Scholar 

  64. Kemphues KJ, Priess JR, Morton DG, Cheng NS (1988) Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52:311–320

    Article  CAS  PubMed  Google Scholar 

  65. Zhang L, Li J, Young LH, Caplan MJ (2006) AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc Natl Acad Sci U S A 103:17272–17277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zheng B, Cantley LC (2007) Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc Natl Acad Sci U S A 104:819–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee JH, Koh H, Kim M, Kim Y, Lee SY, Karess RE, Lee SH, Shong M, Kim JM, Kim J, Chung J (2007) Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447:1017–1020

    Article  CAS  PubMed  Google Scholar 

  68. Mirouse V, Swick LL, Kazgan N, St Johnston D, Brenman JE (2007) LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J Cell Biol 177:387–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hezel AF, Gurumurthy S, Granot Z, Swisa A, Chu GC, Bailey G, Dor Y, Bardeesy N, Depinho RA (2008) Pancreatic LKB1 deletion leads to acinar polarity defects and cystic neoplasms. Mol Cell Biol 28:2414–2425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Partanen JI, Nieminen AI, Makela TP, Klefstrom J (2007) Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization. Proc Natl Acad Sci U S A 104:14694–14699

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Baron A, Migita T, Tang D, Loda M (2004) Fatty acid synthase: a metabolic oncogene in prostate cancer? J Cell Biochem 91:47–53

    Article  CAS  PubMed  Google Scholar 

  72. Zhan Y, Ginanni N, Tota MR, Wu M, Bays NW, Richon VM, Kohl NE, Bachman ES, Strack PR, Krauss S (2008) Control of cell growth and survival by enzymes of the fatty acid synthesis pathway in HCT-116 colon cancer cells. Clin Cancer Res 14:5735–5742

    Article  CAS  PubMed  Google Scholar 

  73. Chajes V, Cambot M, Moreau K, Lenoir GM, Joulin V (2006) Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res 66:5287–5294

    Article  CAS  PubMed  Google Scholar 

  74. Brunet J, Vazquez-Martin A, Colomer R, Grana-Suarez B, Martin-Castillo B, Menendez JA (2008) BRCA1 and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer. Mol Carcinog 47:157–163

    Article  CAS  PubMed  Google Scholar 

  75. Magnard C, Bachelier R, Vincent A, Jaquinod M, Kieffer S, Lenoir GM, Venezia ND (2002) BRCA1 interacts with acetyl-CoA carboxylase through its tandem of BRCT domains. Oncogene 21:6729–6739

    Article  CAS  PubMed  Google Scholar 

  76. Ray H, Moreau K, Dizin E, Callebaut I, Venezia ND (2006) ACCA phosphopeptide recognition by the BRCT repeats of BRCA1. J Mol Biol 359:973–982

    Article  CAS  PubMed  Google Scholar 

  77. Shen Y, Tong L (2008) Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1. Biochemistry 47:5767–5773

    Article  CAS  PubMed  Google Scholar 

  78. Chesney J (2006) 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis. Curr Opin Clin Nutr Metab Care 9:535–539

    Article  CAS  PubMed  Google Scholar 

  79. Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L (2004) 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochem J 381:561–579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Almeida A, Moncada S, Bolanos JP (2004) Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat Cell Biol 6:45–51

    Article  CAS  PubMed  Google Scholar 

  81. Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D, Hue L (2000) Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol 10:1247–1255

    Article  CAS  PubMed  Google Scholar 

  82. Marsin AS, Bouzin C, Bertrand L, Hue L (2002) The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J Biol Chem 277:30778–30783

    Article  CAS  PubMed  Google Scholar 

  83. Goren N, Manzano A, Riera L, Ambrosio S, Ventura F, Bartrons R (2000) 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase expression in rat brain during development. Brain Res Mol Brain Res 75:138–142

    Article  CAS  PubMed  Google Scholar 

  84. Atsumi T, Chesney J, Metz C, Leng L, Donnelly S, Makita Z, Mitchell R, Bucala R (2002) High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res 62:5881–5887

    CAS  PubMed  Google Scholar 

  85. Minchenko A, Leshchinsky I, Opentanova I, Sang N, Srinivas V, Armstead V, Caro J (2002) Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. J Biol Chem 277:6183–6187

    Article  CAS  PubMed  Google Scholar 

  86. Telang S, Yalcin A, Clem AL, Bucala R, Lane AN, Eaton JW, Chesney J (2006) Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 25:7225–7234

    Article  CAS  PubMed  Google Scholar 

  87. Calvo MN, Bartrons R, Castano E, Perales JC, Navarro-Sabate A, Manzano A (2006) PFKFB3 gene silencing decreases glycolysis, induces cell-cycle delay and inhibits anchorage-independent growth in HeLa cells. FEBS Lett 580:3308–3314

    Article  CAS  PubMed  Google Scholar 

  88. Launonen V (2005) Mutations in the human LKB1/STK11 gene. Hum Mutat 26:291–297

    Article  CAS  PubMed  Google Scholar 

  89. Esteller M, Avizienyte E, Corn PG, Lothe RA, Baylin SB, Aaltonen LA, Herman JG (2000) Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Oncogene 19:164–168

    Article  CAS  PubMed  Google Scholar 

  90. Trojan J, Brieger A, Raedle J, Esteller M, Zeuzem S (2000) 5′-CpG island methylation of the LKB1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer. Gut 47:272–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zheng B, Jeong JH, Asara JM, Yuan YY, Granter SR (2009) Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell. Mol Cell 33(2):237–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Esteve-Puig R, Canals F, Colome N, Merlino G, Recio JA (2009) Uncoupling of the LKB1-AMPKalpha energy sensor pathway by growth factors and oncogenic BRAF. PLoS ONE 4:e4771

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Shell SA, Lyass L, Trusk PB, Pry KJ, Wappel RL, Bacus SS (2008) Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle 7:1769–1775

    Article  CAS  PubMed  Google Scholar 

  94. Spector NL, Yarden Y, Smith B, Lyass L, Trusk P, Pry K, Hill JE, Xia W, Seger R, Bacus SS (2007) Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells. Proc Natl Acad Sci U S A 104:10607–10612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bastie CC, Zong H, Xu J, Busa B, Judex S, Kurland IJ, Pessin JE (2007) Integrative metabolic regulation of peripheral tissue fatty acid oxidation by the SRC kinase family member Fyn. Cell Metab 5:371–381

    Article  CAS  PubMed  Google Scholar 

  96. Hurley RL, Barre LK, Wood SD, Anderson KA, Kemp BE, Means AR, Witters LA (2006) Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP. J Biol Chem 281:36662–36672

    Article  CAS  PubMed  Google Scholar 

  97. Qi J, Gong J, Zhao T, Zhao J, Lam P, Ye J, Li JZ, Wu J, Zhou HM, Li P (2008) Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue. EMBO J 27:1537–1548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE, Pour PM (2001) Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 120:1263–1270

    Article  CAS  PubMed  Google Scholar 

  99. Anisimov VN, Egormin PA, Bershtein LM, Zabezhinskii MA, Piskunova TS, Popovich IG, Semenchenko AV (2005) Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice. Bull Exp Biol Med 139:721–723

    Article  CAS  PubMed  Google Scholar 

  100. Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL, McBurnie W, Fleming S, Alessi DR (2008) Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 412:211–221

    Article  CAS  PubMed  Google Scholar 

  101. Tomimoto A, Endo H, Sugiyama M, Fujisawa T, Hosono K, Takahashi H, Nakajima N, Nagashima Y, Wada K, Nakagama H, Nakajima A (2008) Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci 99:2136–2141

    Article  CAS  PubMed  Google Scholar 

  102. Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F (2008) The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27:3576–3586

    Article  CAS  PubMed  Google Scholar 

  103. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, Burchard EG, Brett CM, Giacomini KM (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117:1422–1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305

    Article  PubMed  PubMed Central  Google Scholar 

  105. Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29:254–258

    Article  PubMed  Google Scholar 

  106. Hursting SD, Lashinger LM, Colbert LH, Rogers CJ, Wheatley KW, Nunez NP, Mahabir S, Barrett JC, Forman MR, Perkins SN (2007) Energy balance and carcinogenesis: underlying pathways and targets for intervention. Curr Cancer Drug Targets 7:484–491

    Article  CAS  PubMed  Google Scholar 

  107. Gotlieb WH, Saumet J, Beauchamp MC, Gu J, Lau S, Pollak MN, Bruchim I (2008) In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol 110:246–250

    Article  CAS  PubMed  Google Scholar 

  108. Ashrafian H (2006) Cancer’s sweet tooth: the Janus effect of glucose metabolism in tumorigenesis. Lancet 367:618–621

    Article  CAS  PubMed  Google Scholar 

  109. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 11:891–899

    Article  CAS  Google Scholar 

  110. Shaw RJ. (2006) Glucose metabolism and cancer. Curr Opin Cell Biol 6:598–608

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Kenneth Swanson for critical reading the manuscript. This work is supported by National Institutes of Health Grant GM56203 and CA102694 to L.C.C., and K99CA133245 to B.Z.

Author information

Authors and Affiliations

  1. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Center for Life Sciences, Room 417, 330 Brookline Avenue, Boston, MA, 02115, USA

    Bin Zheng

  2. Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA

    Bin Zheng & Lewis C. Cantley

  3. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Center for Life Sciences, Rm 417, 330 Brookline Avenue, Boston, MA, 02115, USA

    Lewis C. Cantley

Authors
  1. Bin Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lewis C. Cantley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lewis C. Cantley .

Editor information

Editors and Affiliations

  1. Mount Sinai Hospital, Dept. Medicine, University of Toronto, Murray St. 60, Toronto, M5T 3L9, Ontario, Canada

    I. George Fantus

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Zheng, B., Cantley, L.C. (2011). AMP-Activated Protein Kinase and Cancer Cell Metabolism. In: Fantus, I. (eds) Insulin Resistance and Cancer. Energy Balance and Cancer, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9911-5_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-9911-5_9

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-9910-8

  • Online ISBN: 978-1-4419-9911-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation