1932

Abstract

The AMP-activated protein kinase (AMPK) is activated by energy stress and restores homeostasis by switching on catabolism, while switching off cell growth and proliferation. Findings that AMPK acts downstream of the tumor suppressor LKB1 have suggested that AMPK might also suppress tumorigenesis. In mouse models of B and T cell lymphoma in which genetic loss of AMPK occurred before tumor initiation, tumorigenesis was accelerated, confirming that AMPK has tumor-suppressor functions. However, when loss of AMPK in a T cell lymphoma model occurred after tumor initiation, or simultaneously with tumor initiation in a lung cancer model, the disease was ameliorated. Thus, once tumorigenesis has occurred, AMPK switches from tumor suppression to tumor promotion. Analysis of alterations in AMPK genes in human cancers suggests similar dichotomies, with some genes being frequently amplified while others are mutated. Overall, while AMPK-activating drugs might be effective in preventing cancer, in some cases AMPK inhibitors might be required to treat it.

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2020-03-04
2024-04-26
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Literature Cited

  1. Alessi DR, Sakamoto K, Bayascas JR 2006. Lkb1-dependent signaling pathways. Annu. Rev. Biochem. 75:137–63
    [Google Scholar]
  2. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ et al. 2007. The selectivity of protein kinase inhibitors: a further update. Biochem. J. 408:297–315
    [Google Scholar]
  3. Barnes K, Ingram JC, Porras OH, Barros LF, Hudson ER et al. 2002. Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK). J. Cell Sci. 115:2433–42
    [Google Scholar]
  4. Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L et al. 2016. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22:298–305
    [Google Scholar]
  5. Bultot L, Guigas B, Von Wilamowitz-Moellendorff A, Maisin L, Vertommen D et al. 2012. AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase. Biochem. J. 443:193–203
    [Google Scholar]
  6. Cancer Genome Atlas Res. Netw 2014. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543–50
    [Google Scholar]
  7. Carling D. 2017. AMPK signalling in health and disease. Curr. Opin. Cell Biol. 45:31–37
    [Google Scholar]
  8. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO et al. 2012. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–4
    [Google Scholar]
  9. Chen L, Shu Y, Liang X, Chen EC, Yee SW et al. 2014. OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. PNAS 111:9983–88
    [Google Scholar]
  10. Clarke PR, Hardie DG. 1990. Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J 9:2439–46
    [Google Scholar]
  11. Clem B, Telang S, Clem A, Yalcin A, Meier J et al. 2008. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol. Cancer Ther. 7:110–20
    [Google Scholar]
  12. Davies SP, Helps NR, Cohen PTW, Hardie DG 1995. 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2Cα and native bovine protein phosphatase-2AC. FEBS Lett 377:421–25
    [Google Scholar]
  13. Dite TA, Langendorf CG, Hoque A, Galic S, Rebello RJ et al. 2018. AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965. J. Biol. Chem. 293:8874–85
    [Google Scholar]
  14. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA et al. 2011. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–61
    [Google Scholar]
  15. Eichner LJ, Brun SN, Herzig S, Young NP, Curtis SD et al. 2019. Genetic analysis reveals AMPK is required to support tumor growth in murine Kras-dependent lung cancer models. Cell Metab 29:285–302.e7Found that AMPK is a tumor promoter; genetic loss simultaneous with tumorigenesis reduces murine non-small-cell lung cancer.
    [Google Scholar]
  16. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD 2005. Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–5
    [Google Scholar]
  17. Faubert B, Boily G, Izreig S, Griss T, Samborska B et al. 2012. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17:113–24Found that AMPK is a tumor suppressor; genetic loss prior to development of B cell lymphoma accelerates disease.
    [Google Scholar]
  18. Fogarty S, Ross FA, Vara Ciruelos D, Gray A, Gowans GJ, Hardie DG 2016. AMPK causes cell cycle arrest in LKB1-deficient cells via activation of CAMKK2. Mol. Cancer Res. 14:683–95
    [Google Scholar]
  19. Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T et al. 2013. Single phosphorylation sites in ACC1 and ACC2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19:1649–54
    [Google Scholar]
  20. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B et al. 2013. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal 6:pl1
    [Google Scholar]
  21. Goodwin JM, Svensson RU, Lou HJ, Winslow MM, Turk BE, Shaw RJ 2014. An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential. Mol. Cell 55:436–50Found that LKB1 represses expression of Snail1, which promotes epithelial-to-mesenchymal transition, invasion, and metastasis, via an AMPK-independent mechanism.
    [Google Scholar]
  22. Gowans GJ, Hawley SA, Ross FA, Hardie DG 2013. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab 18:556–66
    [Google Scholar]
  23. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A et al. 2008. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30:214–26
    [Google Scholar]
  24. Hardie DG, Alessi DR. 2013. LKB1 and AMPK and the cancer-metabolism link—ten years after. BMC Biol 11:36
    [Google Scholar]
  25. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L et al. 2003. Complexes between the LKB1 tumor suppressor, STRADa/b and MO25a/b are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2:28
    [Google Scholar]
  26. Hawley SA, Davison M, Woods A, Davies SP, Beri RK et al. 1996. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem. 271:27879–87
    [Google Scholar]
  27. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J et al. 2005. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9–19
    [Google Scholar]
  28. Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A et al. 2010. Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11:554–65
    [Google Scholar]
  29. Herzig S, Shaw RJ. 2017. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19:121–35
    [Google Scholar]
  30. Hoppe S, Bierhoff H, Cado I, Weber A, Tiebe M et al. 2009. AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply. PNAS 106:17781–86
    [Google Scholar]
  31. Houde VP, Donzelli S, Sacconi A, Galic S, Hammill JA et al. 2017. AMPK β1 reduces tumor progression and improves survival in p53 null mice. Mol. Oncol. 11:1143–55
    [Google Scholar]
  32. Hudson ER, Pan DA, James J, Lucocq JM, Hawley SA et al. 2003. A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr. Biol. 13:861–66
    [Google Scholar]
  33. 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. 280:29060–66
    [Google Scholar]
  34. Imamura K, Ogura T, Kishimoto A, Kaminishi M, Esumi H 2001. Cell cycle regulation via p53 phosphorylation by a 5′-AMP activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, in a human hepatocellular carcinoma cell line. Biochem. Biophys. Res. Commun. 287:562–67
    [Google Scholar]
  35. Inoki K, Zhu T, Guan KL 2003. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–90
    [Google Scholar]
  36. Jaleel M, McBride A, Lizcano JM, Deak M, Toth R et al. 2005. Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate. FEBS Lett 579:1417–23
    [Google Scholar]
  37. Jeon SM, Chandel NS, Hay N 2012. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485:661–65
    [Google Scholar]
  38. Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K et al. 2007. LKB1 modulates lung cancer differentiation and metastasis. Nature 448:807–10
    [Google Scholar]
  39. Johanns M, Pyr Dit Ruys S, Houddane A, Vertommen D, Herinckx G et al. 2017. Direct and indirect activation of eukaryotic elongation factor 2 kinase by AMP-activated protein kinase. Cell Signal 36:212–21
    [Google Scholar]
  40. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J et al. 2005. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18:283–93
    [Google Scholar]
  41. Jorgensen SB, Nielsen JN, Birk JB, Olsen GS, Viollet B et al. 2004. The α2–5′AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading. Diabetes 53:3074–81
    [Google Scholar]
  42. Kazgan N, Williams T, Forsberg LJ, Brenman JE 2010. Identification of a nuclear export signal in the catalytic subunit of AMP-activated protein kinase. Mol. Biol. Cell 21:3433–42
    [Google Scholar]
  43. Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA et al. 2016. AMPK is essential to balance glycolysis and mitochondrial metabolism to control T-ALL cell stress and survival. Cell Metab 23:649–62Found that AMPK is a tumor promoter; AMPK loss after development of T cell lymphoma ameliorates disease.
    [Google Scholar]
  44. Kordes S, Pollak MN, Zwinderman AH, Mathot RA, Weterman MJ et al. 2015. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 16:839–47
    [Google Scholar]
  45. Lin SC, Hardie DG. 2017. AMPK: sensing glucose as well as cellular energy status. Cell Metab 27:299–313
    [Google Scholar]
  46. Liu L, Ulbrich J, Muller J, Wustefeld T, Aeberhard L et al. 2012. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 483:608–12
    [Google Scholar]
  47. Lizcano JM, Göransson O, Toth R, Deak M, Morrice NA et al. 2004. LKB1 is a master kinase that activates 13 protein kinases of the AMPK subfamily, including the MARK/PAR-1 kinases. EMBO J 23:833–43
    [Google Scholar]
  48. Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C et al. 2000. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr. Biol. 10:1247–55
    [Google Scholar]
  49. 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. 277:30778–83
    [Google Scholar]
  50. Merrill GM, Kurth E, Hardie DG, Winder WW 1997. AICAR decreases malonyl-CoA and increases fatty acid oxidation in skeletal muscle of the rat. Am. J. Physiol. 273:E1107–12
    [Google Scholar]
  51. Munday MR, Campbell DG, Carling D, Hardie DG 1988. Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur. J. Biochem. 175:331–38
    [Google Scholar]
  52. Muoio DM, Seefeld K, Witters LA, Coleman RA 1999. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem. J. 338:783–91
    [Google Scholar]
  53. Noto H, Goto A, Tsujimoto T, Noda M 2012. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLOS ONE 7:e33411
    [Google Scholar]
  54. Oakhill JS, Steel R, Chen ZP, Scott JW, Ling N et al. 2011. AMPK is a direct adenylate charge-regulated protein kinase. Science 332:1433–35
    [Google Scholar]
  55. Pehmoller C, Treebak JT, Birk JB, Chen S, Mackintosh C et al. 2009. Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14–3–3 binding in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 297:E665–75
    [Google Scholar]
  56. Penfold L, Woods A, Muckett P, Nikitin AY, Kent TR et al. 2018. CAMKK2 promotes prostate cancer independently of AMPK via increased lipogenesis. Cancer Res 78:6747–61
    [Google Scholar]
  57. Phoenix KN, Devarakonda CV, Fox MM, Stevens LE, Claffey KP 2012. AMPKα2 suppresses murine embryonic fibroblast transformation and tumorigenesis. Genes Cancer 3:51–62
    [Google Scholar]
  58. Pineda CT, Ramanathan S, Fon Tacer K, Weon JL, Potts MB et al. 2015. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 160:715–28
    [Google Scholar]
  59. Pollak MN. 2012. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2:778–90
    [Google Scholar]
  60. Qian X, Li X, Tan L, Lee JH, Xia Y et al. 2018. Conversion of PRPS hexamer to monomer by AMPK-mediated phosphorylation inhibits nucleotide synthesis in response to energy stress. Cancer Discov 8:94–107
    [Google Scholar]
  61. Rattan R, Giri S, Singh AK, Singh I 2005. 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J. Biol. Chem. 280:39582–93
    [Google Scholar]
  62. Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA 2013. AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur. J. Immunol. 43:889–96
    [Google Scholar]
  63. Ross FA, Jensen TE, Hardie DG 2016a. Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. Biochem. J. 473:189–99
    [Google Scholar]
  64. Ross FA, MacKintosh C, Hardie DG 2016b. AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours. FEBS J 283:2987–3001
    [Google Scholar]
  65. Salt IP, Celler JW, Hawley SA, Prescott A, Woods A et al. 1998. AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the α2 isoform. Biochem. J. 334:177–87
    [Google Scholar]
  66. Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B et al. 2002. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 62:3659–62
    [Google Scholar]
  67. Scott JW, Galic S, Graham KL, Foitzik R, Ling NX et al. 2015. Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release. Chem. Biol. 22:705–11
    [Google Scholar]
  68. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA et al. 2004. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. PNAS 101:3329–35
    [Google Scholar]
  69. Speidel D. 2015. The role of DNA damage responses in p53 biology. Arch. Toxicol. 89:501–17
    [Google Scholar]
  70. Stahmann N, Woods A, Carling D, Heller R 2006. Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase β. Mol. Cell. Biol. 26:5933–45
    [Google Scholar]
  71. Stahmann N, Woods A, Spengler K, Heslegrave A, Bauer R et al. 2010. Activation of AMP-activated protein kinase by vascular endothelial growth factor mediates endothelial angiogenesis independently of nitric-oxide synthase. J. Biol. Chem. 285:10638–52
    [Google Scholar]
  72. Toyama EQ, Herzig S, Courchet J, Lewis TL Jr., Loson OC et al. 2016. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351:275–81
    [Google Scholar]
  73. Vara-Ciruelos D, Dandapani M, Gray A, Egbani EO, Evans AM, Hardie DG 2018a. Genotoxic damage activates the AMPK-α1 isoform in the nucleus via Ca2+/CaMKK2 signaling to enhance tumor cell survival. Mol. Cancer Res. 16:345–57
    [Google Scholar]
  74. Vara-Ciruelos D, Dandapani M, Grzes KM, Atrih A, Foretz M et al. 2018b. Phenformin, but not metformin, delays development of T-cell acute lymphoblastic leukemia/lymphoma via cell-autonomous activation of AMPK. Cell Rep 27:690–98Found that AMPK is a tumor suppressor that protects against T cell lymphoma; AMPK activation using phenformin enhances protection.
    [Google Scholar]
  75. Vila IK, Yao Y, Kim G, Xia W, Kim H et al. 2017. A UBE2O-AMPKα2 axis that promotes tumor initiation and progression offers opportunities for therapy. Cancer Cell 31:208–24
    [Google Scholar]
  76. Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO 2000. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J. Appl. Physiol. 88:2219–26
    [Google Scholar]
  77. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M et al. 2005. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2:21–33
    [Google Scholar]
  78. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG et al. 2003. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13:2004–8
    [Google Scholar]
  79. Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C et al. 2013. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol. Cell 49:1167–75
    [Google Scholar]
  80. Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV et al. 2011. Structure of mammalian AMPK and its regulation by ADP. Nature 472:230–33
    [Google Scholar]
  81. Yang Y, Atasoy D, Su HH, Sternson SM 2011. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146:992–1003
    [Google Scholar]
  82. Yi M, Ban Y, Tan Y, Xiong W, Li G, Xiang B 2019. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4: a pair of valves for fine-tuning of glucose metabolism in human cancer. Mol. Metab. 20:1–13
    [Google Scholar]
  83. Zhang CS, Hawley SA, Zong Y, Li M, Wang Z et al. 2017. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548:112–16
    [Google Scholar]
  84. Zhou G, Myers R, Li Y, Chen Y, Shen X et al. 2001. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Investig. 108:1167–74
    [Google Scholar]
  85. 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
    [Google Scholar]
  86. Zong H, Ren JM, Young LH, Pypaert M, Mu J et al. 2002. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. PNAS 99:15983–87
    [Google Scholar]
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