Home LiteratureArticle Details
PMID: 19629071 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The LKB1-AMPK pathway: metabolism and growth control in tumour suppression.

Nature reviews. Cancer ·Vol. 9 ·No. 8 ·2009-00-00 ·Pages 563-75

Shackelford DB, Shaw RJ

Abstract

In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a serine-threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.

MeSH Terms
AMP-Activated Protein Kinase Kinases AMP-Activated Protein Kinases/drug effects,physiology Animals Blood Glucose/metabolism Disease Models, Animal Humans Hypoglycemic Agents/pharmacology Mice Neoplasms/drug therapy,metabolism,pathology Protein Kinase Inhibitors/therapeutic use Protein Kinases/physiology Protein Serine-Threonine Kinases/drug effects,physiology Signal Transduction/physiology TOR Serine-Threonine Kinases
Chemicals
Blood Glucose Hypoglycemic Agents Protein Kinase Inhibitors Protein Kinases MTOR protein, human mTOR protein, mouse Protein Serine-Threonine Kinases STK11 protein, human TOR Serine-Threonine Kinases AMP-Activated Protein Kinase Kinases AMP-Activated Protein Kinases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Shackelford David B
Dulbecco Center for Cancer Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Shaw Reuben J
References (200)
200 references, click to expand
  1. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action.
    J Clin Invest. 2007 May;117(5):1422-31 PMID: 17476361
  2. Cell cycle regulation via p53 phosphorylation by a 5'-AMP activated protein kinase activator, 5-aminoimidazole- 4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line.
    Biochem Biophys Res Commun. 2001 Sep 21;287(2):562-7 PMID: 11554766
  3. Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas.
    Cancer Res. 2008 Feb 1;68(3):759-66 PMID: 18245476
  4. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis.
    N Engl J Med. 2008 Jan 10;358(2):200-3 PMID: 18184971
  5. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase.
    Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):819-22 PMID: 17204563
  6. Using kinomics to delineate signaling pathways: control of CRTC2/TORC2 by the AMPK family.
    Cell Cycle. 2008 Dec 15;7(24):3823-8 PMID: 19098422
  7. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.
    Genes Dev. 2004 Dec 1;18(23):2893-904 PMID: 15545625
  8. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.
    Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15552-7 PMID: 17028174
  9. AMP-activated protein kinase-regulated phosphorylation and acetylation of importin alpha1: involvement in the nuclear import of RNA-binding protein HuR.
    J Biol Chem. 2004 Nov 12;279(46):48376-88 PMID: 15342649
  10. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.
    PLoS Med. 2008 Jan 22;5(1):e8 PMID: 18215105
  11. mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome.
    Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11137-42 PMID: 19541609
  12. AMP-activated protein kinase as a drug target.
    Annu Rev Pharmacol Toxicol. 2007;47:185-210 PMID: 16879084
  13. LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis.
    Cancer Res. 2008 Jan 1;68(1):55-63 PMID: 18172296
  14. Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation.
    EMBO J. 2005 Jul 6;24(13):2391-402 PMID: 15961999
  15. Regulation of planar cell polarity by Smurf ubiquitin ligases.
    Cell. 2009 Apr 17;137(2):295-307 PMID: 19379695
  16. Adiponectin inhibits colorectal cancer cell growth through the AMPK/mTOR pathway.
    Int J Oncol. 2009 Feb;34(2):339-44 PMID: 19148467
  17. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth.
    Cell. 2006 Sep 8;126(5):955-68 PMID: 16959574
  18. Drosophila PAR-1 and 14-3-3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells.
    Cell. 2003 Dec 12;115(6):691-704 PMID: 14675534
  19. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth.
    Mol Cancer Ther. 2008 Jan;7(1):110-20 PMID: 18202014
  20. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector.
    Cell. 2004 Oct 1;119(1):61-74 PMID: 15454081
  21. Ras, PI(3)K and mTOR signalling controls tumour cell growth.
    Nature. 2006 May 25;441(7092):424-30 PMID: 16724053
  22. Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival.
    Cancer Res. 2006 May 15;66(10):5287-94 PMID: 16707454
  23. Role of AMP-activated protein kinase in mechanism of metformin action.
    J Clin Invest. 2001 Oct;108(8):1167-74 PMID: 11602624
  24. Mimicry of a cellular low energy status blocks tumor cell anabolism and suppresses the malignant phenotype.
    Cancer Res. 2005 Mar 15;65(6):2441-8 PMID: 15781660
  25. Somatic LKB1 mutations promote cervical cancer progression.
    PLoS One. 2009;4(4):e5137 PMID: 19340305
  26. Insulin and insulin-like growth factor signalling in neoplasia.
    Nat Rev Cancer. 2008 Dec;8(12):915-28 PMID: 19029956
  27. Diet and cancer prevention: the roles of observation and experimentation.
    Nat Rev Cancer. 2008 Sep;8(9):694-703 PMID: 19143054
  28. Increased AMP:ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function.
    J Biol Chem. 2003 Jul 18;278(29):27016-23 PMID: 12730239
  29. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice.
    Science. 2001 Aug 17;293(5533):1323-6 PMID: 11509733
  30. The polarity-inducing kinase Par-1 controls Xenopus gastrulation in cooperation with 14-3-3 and aPKC.
    EMBO J. 2004 Oct 27;23(21):4190-201 PMID: 15343271
  31. The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole.
    Cell. 2000 May 12;101(4):377-88 PMID: 10830165
  32. DNA double-strand breaks: signaling, repair and the cancer connection.
    Nat Genet. 2001 Mar;27(3):247-54 PMID: 11242102
  33. AMPK phosphorylation of raptor mediates a metabolic checkpoint.
    Mol Cell. 2008 Apr 25;30(2):214-26 PMID: 18439900
  34. Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta.
    Mol Cell Biol. 2006 Aug;26(16):5933-45 PMID: 16880506
  35. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1.
    EMBO J. 2004 Feb 25;23(4):833-43 PMID: 14976552
  36. Energy-dependent regulation of cell structure by AMP-activated protein kinase.
    Nature. 2007 Jun 21;447(7147):1017-20 PMID: 17486097
  37. Mechanisms linking physical activity with cancer.
    Nat Rev Cancer. 2008 Mar;8(3):205-11 PMID: 18235448
  38. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
    Mol Cell. 2008 May 23;30(4):393-402 PMID: 18498744
  39. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis.
    Nat Cell Biol. 2007 Feb;9(2):218-24 PMID: 17237771
  40. LKB1 and AMPK maintain epithelial cell polarity under energetic stress.
    J Cell Biol. 2007 May 7;177(3):387-92 PMID: 17470638
  41. AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5.
    Diabetes. 2008 Apr;57(4):860-7 PMID: 18184930
  42. LKB1 modulates lung cancer differentiation and metastasis.
    Nature. 2007 Aug 16;448(7155):807-10 PMID: 17676035
  43. HIF-1 mediates the Warburg effect in clear cell renal carcinoma.
    J Bioenerg Biomembr. 2007 Jun;39(3):231-4 PMID: 17551816
  44. SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes.
    Nat Med. 2007 May;13(5):597-603 PMID: 17468767
  45. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase.
    Cancer Prev Res (Phila). 2008 Oct;1(5):369-75 PMID: 19138981
  46. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice.
    Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10320-5 PMID: 11504907
  47. PAR-1 kinase phosphorylates Dlg and regulates its postsynaptic targeting at the Drosophila neuromuscular junction.
    Neuron. 2007 Jan 18;53(2):201-15 PMID: 17224403
  48. Glucose metabolism and cancer.
    Curr Opin Cell Biol. 2006 Dec;18(6):598-608 PMID: 17046224
  49. The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge.
    Oncogene. 2007 Apr 5;26(16):2272-82 PMID: 17043654
  50. The glycogen-binding domain on the AMPK beta subunit allows the kinase to act as a glycogen sensor.
    Cell Metab. 2009 Jan 7;9(1):23-34 PMID: 19117544
  51. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
    PLoS Biol. 2009 Feb 10;7(2):e38 PMID: 19209957
  52. 14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK.
    J Cell Sci. 2005 Dec 1;118(Pt 23):5661-73 PMID: 16306228
  53. PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling.
    Nat Cell Biol. 2001 Jul;3(7):628-36 PMID: 11433294
  54. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.
    Nature. 2009 Apr 23;458(7241):1056-60 PMID: 19262508
  55. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways.
    Cancer Res. 2007 Apr 1;67(7):3043-53 PMID: 17409411
  56. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation.
    Mol Cell. 2009 Jan 30;33(2):237-47 PMID: 19187764
  57. Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control.
    Nat Cell Biol. 2006 Nov;8(11):1235-45 PMID: 17060907
  58. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation.
    Nature. 2002 Sep 12;419(6903):162-7 PMID: 12226664
  59. AMP-activated protein kinase signaling results in cytoplasmic sequestration of p27.
    Cancer Res. 2008 Aug 15;68(16):6496-506 PMID: 18701472
  60. Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity.
    J Cell Biol. 2007 Jul 30;178(3):355-61 PMID: 17646398
  61. Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate.
    FEBS Lett. 2005 Feb 28;579(6):1417-23 PMID: 15733851
  62. Hypoxia-induced energy stress regulates mRNA translation and cell growth.
    Mol Cell. 2006 Feb 17;21(4):521-31 PMID: 16483933
  63. Prevention of pancreatic cancer induction in hamsters by metformin.
    Gastroenterology. 2001 Apr;120(5):1263-70 PMID: 11266389
  64. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice.
    Biochem J. 2008 Jun 1;412(2):211-21 PMID: 18387000
  65. Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer.
    Oncogene. 2007 Mar 8;26(11):1616-25 PMID: 16953221
  66. The LKB1 tumor suppressor negatively regulates mTOR signaling.
    Cancer Cell. 2004 Jul;6(1):91-9 PMID: 15261145
  67. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis.
    FEBS Lett. 1987 Nov 2;223(2):217-22 PMID: 2889619
  68. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity.
    Nature. 2003 Jan 23;421(6921):379-84 PMID: 12540903
  69. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway.
    Nat Cell Biol. 2004 Jan;6(1):45-51 PMID: 14688792
  70. Defining the role of mTOR in cancer.
    Cancer Cell. 2007 Jul;12(1):9-22 PMID: 17613433
  71. A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis.
    Biochem J. 2008 Nov 15;416(1):1-14 PMID: 18774945
  72. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors.
    J Biol Chem. 2001 Oct 19;276(42):38341-4 PMID: 11518699
  73. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome.
    Genes Dev. 2004 Jul 1;18(13):1533-8 PMID: 15231735
  74. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity.
    Nature. 2007 May 17;447(7142):330-3 PMID: 17507984
  75. Metformin and reduced risk of cancer in diabetic patients.
    BMJ. 2005 Jun 4;330(7503):1304-5 PMID: 15849206
  76. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro.
    Toxicol Appl Pharmacol. 2008 Dec 1;233(2):203-10 PMID: 18817800
  77. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD.
    Cell. 2004 Feb 6;116(3):457-66 PMID: 15016379
  78. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.
    Nature. 1998 Jan 8;391(6663):184-7 PMID: 9428765
  79. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity.
    J Biol Chem. 2005 Sep 16;280(37):32081-9 PMID: 16027121
  80. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor.
    J Biol Chem. 2007 Oct 12;282(41):30107-19 PMID: 17711846
  81. Mst4 and Ezrin induce brush borders downstream of the Lkb1/Strad/Mo25 polarization complex.
    Dev Cell. 2009 Apr;16(4):551-62 PMID: 19386264
  82. LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis.
    Nat Genet. 2008 Apr;40(4):455-9 PMID: 18311138
  83. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways.
    Nat Med. 2004 Jun;10(6):594-601 PMID: 15156201
  84. Structural basis for AMP binding to mammalian AMP-activated protein kinase.
    Nature. 2007 Sep 27;449(7161):496-500 PMID: 17851531
  85. Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways.
    Genes Dev. 2006 Feb 1;20(3):267-75 PMID: 16452501
  86. AMP-activated protein kinase phosphorylates and desensitizes smooth muscle myosin light chain kinase.
    J Biol Chem. 2008 Jul 4;283(27):18505-12 PMID: 18426792
  87. Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization.
    Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14694-9 PMID: 17766436
  88. Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes.
    Chem Biol. 2008 Nov 24;15(11):1220-30 PMID: 19022182
  89. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin.
    Diabetes Care. 2006 Feb;29(2):254-8 PMID: 16443869
  90. The coactivator CRTC1 promotes cell proliferation and transformation via AP-1.
    Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1445-50 PMID: 19164581
  91. Targeted cancer therapies based on the inhibition of DNA strand break repair.
    Oncogene. 2007 Dec 10;26(56):7816-24 PMID: 18066095
  92. Metformin in breast cancer: time for action.
    J Clin Oncol. 2009 Jul 10;27(20):3271-3 PMID: 19487373
  93. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling.
    Cell. 2008 Aug 8;134(3):451-60 PMID: 18692468
  94. Effects of metformin on mammalian target of rapamycin in a mouse model of endometrial hyperplasia.
    Eur J Obstet Gynecol Reprod Biol. 2009 Aug;145(2):195-9 PMID: 19501448
  95. Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2.
    Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10161-6 PMID: 18626018
  96. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases.
    Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8839-43 PMID: 12847291
  97. Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models.
    Genes Chromosomes Cancer. 2005 Mar;42(3):213-27 PMID: 15578690
  98. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer.
    J Clin Oncol. 2009 Jul 10;27(20):3297-302 PMID: 19487376
  99. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells.
    Cancer Res. 2006 Nov 1;66(21):10269-73 PMID: 17062558
  100. TSC2 regulates VEGF through mTOR-dependent and -independent pathways.
    Cancer Cell. 2003 Aug;4(2):147-58 PMID: 12957289
  101. LKB1; linking cell structure and tumor suppression.
    Oncogene. 2008 Nov 24;27(55):6908-19 PMID: 19029933
  102. Identification of a novel substrate for TNFalpha-induced kinase NUAK2.
    Biochem Biophys Res Commun. 2008 Jan 18;365(3):541-7 PMID: 18023418
  103. Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis.
    Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12327-32 PMID: 12218179
  104. Novel splice isoforms of STRADalpha differentially affect LKB1 activity, complex assembly and subcellular localization.
    Cancer Biol Ther. 2007 Oct;6(10):1627-31 PMID: 17921699
  105. Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene.
    Oncogene. 2004 May 13;23(22):4037-40 PMID: 15021901
  106. Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development.
    Dev Cell. 2005 Jun;8(6):829-41 PMID: 15935773
  107. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.
    Nature. 2005 Oct 20;437(7062):1109-11 PMID: 16148943
  108. LKB1-dependent signaling pathways.
    Annu Rev Biochem. 2006;75:137-63 PMID: 16756488
  109. A Drosophila melanogaster homologue of Caenorhabditis elegans par-1 acts at an early step in embryonic-axis formation.
    Nat Cell Biol. 2000 Jul;2(7):458-60 PMID: 10878812
  110. Characterization of an alternative splice variant of LKB1.
    J Biol Chem. 2009 Jan 2;284(1):67-76 PMID: 18854309
  111. The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death.
    Mol Cell. 2001 Jun;7(6):1307-19 PMID: 11430832
  112. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis.
    Nat Rev Cancer. 2007 Oct;7(10):763-77 PMID: 17882277
  113. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation.
    Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17414-9 PMID: 18955708
  114. aPKC acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity.
    Curr Biol. 2004 Aug 24;14(16):1425-35 PMID: 15324659
  115. New role for hPar-1 kinases EMK and C-TAK1 in regulating localization and activity of class IIa histone deacetylases.
    Mol Cell Biol. 2006 Oct;26(19):7086-102 PMID: 16980613
  116. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation.
    Oncogene. 2005 Jun 16;24(26):4165-73 PMID: 15806154
  117. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes.
    Cancer Cell. 2004 Jul;6(1):7-10 PMID: 15261137
  118. Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity.
    Mol Biol Cell. 2002 Nov;13(11):4013-28 PMID: 12429843
  119. Suppression of tubulin polymerization by the LKB1-microtubule-associated protein/microtubule affinity-regulating kinase signaling.
    J Biol Chem. 2007 Aug 10;282(32):23532-40 PMID: 17573348
  120. 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. 2003;2(4):28 PMID: 14511394
  121. Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non small cell lung cancer cells.
    Cancer Res. 2008 Jan 15;68(2):580-8 PMID: 18199555
  122. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.
    Exp Gerontol. 2005 Aug-Sep;40(8-9):685-93 PMID: 16125352
  123. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase.
    Oncogene. 2006 Nov 23;25(55):7225-34 PMID: 16715124
  124. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues.
    Cancer Prev Res (Phila). 2008 Jun;1(1):65-76 PMID: 19138937
  125. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth.
    Endocr Relat Cancer. 2008 Sep;15(3):833-9 PMID: 18469156
  126. LKB1 (XEEK1) regulates Wnt signalling in vertebrate development.
    Nat Cell Biol. 2003 Oct;5(10):889-94 PMID: 12973359
  127. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells.
    Cancer Res. 2007 Sep 1;67(17):8180-7 PMID: 17804731
  128. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth.
    Cancer Res. 2007 Jul 15;67(14):6745-52 PMID: 17638885
  129. TSC2 mediates cellular energy response to control cell growth and survival.
    Cell. 2003 Nov 26;115(5):577-90 PMID: 14651849
  130. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade.
    Biochem J. 2007 Apr 1;403(1):139-48 PMID: 17147517
  131. LKB1 regulates neuronal migration and neuronal differentiation in the developing neocortex through centrosomal positioning.
    J Neurosci. 2007 Oct 24;27(43):11769-75 PMID: 17959818
  132. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia.
    Curr Biol. 2000 Oct 19;10(20):1247-55 PMID: 11069105
  133. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung.
    Cancer Res. 2002 Jul 1;62(13):3659-62 PMID: 12097271
  134. How does SIRT1 affect metabolism, senescence and cancer?
    Nat Rev Cancer. 2009 Feb;9(2):123-8 PMID: 19132007
  135. Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer.
    Clin Cancer Res. 2005 Aug 15;11(16):5784-92 PMID: 16115917
  136. Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity.
    Curr Biol. 2004 Apr 20;14(8):736-41 PMID: 15084291
  137. The polarity protein Par6 induces cell proliferation and is overexpressed in breast cancer.
    Cancer Res. 2008 Oct 15;68(20):8201-9 PMID: 18922891
  138. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade.
    Curr Biol. 2003 Nov 11;13(22):2004-8 PMID: 14614828
  139. AMP-activated protein kinase regulates the assembly of epithelial tight junctions.
    Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17272-7 PMID: 17088526
  140. Role of AMP-activated protein kinase in healthy and diseased hearts.
    Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2557-69 PMID: 16844922
  141. Control of cell growth and survival by enzymes of the fatty acid synthesis pathway in HCT-116 colon cancer cells.
    Clin Cancer Res. 2008 Sep 15;14(18):5735-42 PMID: 18794082
  142. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth.
    Biochem J. 2008 Jun 1;412(2):179-90 PMID: 18466115
  143. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.
    Biochem J. 2000 Jun 15;348 Pt 3:607-14 PMID: 10839993
  144. Management of cellular energy by the AMP-activated protein kinase system.
    FEBS Lett. 2003 Jul 3;546(1):113-20 PMID: 12829246
  145. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
    N Engl J Med. 2007 May 31;356(22):2271-81 PMID: 17538086
  146. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice.
    Cancer Res. 2002 Apr 15;62(8):2261-6 PMID: 11956081
  147. Adiponectin and cancer: a systematic review.
    Br J Cancer. 2006 May 8;94(9):1221-5 PMID: 16570048
  148. The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry.
    Development. 2000 Apr;127(7):1467-75 PMID: 10704392
  149. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase.
    Cell Metab. 2005 Jul;2(1):9-19 PMID: 16054095
  150. 5'-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments.
    Mol Cell Biol. 2006 Jul;26(14):5336-47 PMID: 16809770
  151. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.
    Cell Metab. 2008 Sep;8(3):224-36 PMID: 18762023
  152. Regulation of LKB1/STRAD localization and function by E-cadherin.
    Curr Biol. 2009 Jan 13;19(1):37-42 PMID: 19110428
  153. Dietary energy restriction modulates the activity of AMP-activated protein kinase, Akt, and mammalian target of rapamycin in mammary carcinomas, mammary gland, and liver.
    Cancer Res. 2008 Jul 1;68(13):5492-9 PMID: 18593953
  154. Role of Lkb1, the causative gene of Peutz-Jegher's syndrome, in embryogenesis and polyposis.
    Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8903-8 PMID: 12060709
  155. Suppression of Peutz-Jeghers polyposis by targeting mammalian target of rapamycin signaling.
    Clin Cancer Res. 2008 Feb 15;14(4):1167-71 PMID: 18281551
  156. Cell polarity and cancer--cell and tissue polarity as a non-canonical tumor suppressor.
    J Cell Sci. 2008 Apr 15;121(Pt 8):1141-50 PMID: 18388309
  157. Interference with energy metabolism by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside induces HPV suppression in cervical carcinoma cells and apoptosis in the absence of LKB1.
    Biochem J. 2007 May 1;403(3):501-10 PMID: 17212587
  158. Neither LKB1 nor AMPK are the direct targets of metformin.
    Gastroenterology. 2006 Sep;131(3):973; author reply 974-5 PMID: 16952573
  159. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.
    Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12017-22 PMID: 17609368
  160. Lkb1 is required for TGFbeta-mediated myofibroblast differentiation.
    J Cell Sci. 2008 Nov 1;121(Pt 21):3531-40 PMID: 18840652
  161. Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells.
    Cell Cycle. 2008 Jun 15;7(12):1769-75 PMID: 18594201
  162. AMP-activated protein kinase: a universal regulator of autophagy?
    Autophagy. 2007 Jul-Aug;3(4):381-3 PMID: 17457036
  163. LKB1/STRAD promotes axon initiation during neuronal polarization.
    Cell. 2007 May 4;129(3):565-77 PMID: 17482549
  164. 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. 2004 Mar 9;101(10):3329-35 PMID: 14985505
  165. Mechanism by which metformin reduces glucose production in type 2 diabetes.
    Diabetes. 2000 Dec;49(12):2063-9 PMID: 11118008
  166. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.
    Cell. 2005 Nov 18;123(4):569-80 PMID: 16286006
  167. Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-CoA reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion.
    Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9261-5 PMID: 8415689
  168. Lkb1 deficiency causes prostate neoplasia in the mouse.
    Cancer Res. 2008 Apr 1;68(7):2223-32 PMID: 18381428
  169. Lkb1 deficiency alters goblet and paneth cell differentiation in the small intestine.
    PLoS One. 2009;4(1):e4264 PMID: 19165340
  170. LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons.
    Cell. 2007 May 4;129(3):549-63 PMID: 17482548
  171. Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1).
    Hum Mol Genet. 2002 Jun 15;11(13):1497-504 PMID: 12045203
  172. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5.
    Brain. 2007 Jul;130(Pt 7):1929-41 PMID: 17522105
  173. Hypoxia, HIF1 and glucose metabolism in the solid tumour.
    Nat Rev Cancer. 2008 Sep;8(9):705-13 PMID: 19143055
  174. Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer.
    Obes Rev. 2007 Sep;8(5):395-408 PMID: 17716297
  175. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases.
    J Biol Chem. 2005 Aug 12;280(32):29060-6 PMID: 15980064
  176. The tumor suppressor LKB1 regulates lung cancer cell polarity by mediating cdc42 recruitment and activity.
    Cancer Res. 2008 Feb 1;68(3):740-8 PMID: 18245474
  177. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis.
    N Engl J Med. 2008 Jan 10;358(2):140-51 PMID: 18184959
  178. Pancreatic LKB1 deletion leads to acinar polarity defects and cystic neoplasms.
    Mol Cell Biol. 2008 Apr;28(7):2414-25 PMID: 18227155
  179. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes.
    J Exp Med. 2006 Jul 10;203(7):1665-70 PMID: 16818670
  180. Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/-p53-/- compound mutant mice.
    Oncogene. 2006 Mar 16;25(12):1816-20 PMID: 16278673
  181. Selective inhibition of fatty acid synthase for lung cancer treatment.
    Clin Cancer Res. 2007 Dec 1;13(23):7139-45 PMID: 18056164
  182. Oral rapamycin reduces tumour burden and vascularization in Lkb1(+/-) mice.
    J Pathol. 2009 Sep;219(1):35-40 PMID: 19434632
  183. The regulation of AMP-activated protein kinase by upstream kinases.
    Int J Obes (Lond). 2008 Sep;32 Suppl 4:S55-9 PMID: 18719600
  184. TORC1 is essential for NF1-associated malignancies.
    Curr Biol. 2008 Jan 8;18(1):56-62 PMID: 18164202
  185. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.
    Cell Metab. 2006 Jun;3(6):403-16 PMID: 16753576
  186. Hypothalamic CaMKK2 contributes to the regulation of energy balance.
    Cell Metab. 2008 May;7(5):377-88 PMID: 18460329
  187. Dishevelled promotes axon differentiation by regulating atypical protein kinase C.
    Nat Cell Biol. 2007 Jul;9(7):743-54 PMID: 17558396
  188. Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis.
    Cancer Res. 2005 Dec 15;65(24):11297-303 PMID: 16357136
  189. PAR1b promotes cell-cell adhesion and inhibits dishevelled-mediated transformation of Madin-Darby canine kidney cells.
    Mol Biol Cell. 2006 Aug;17(8):3345-55 PMID: 16707567
  190. Role of LKB1 in lung cancer development.
    Br J Cancer. 2008 Sep 2;99(5):683-8 PMID: 18728656
  191. An E2F1-dependent gene expression program that determines the balance between proliferation and cell death.
    Cancer Cell. 2008 Jan;13(1):11-22 PMID: 18167336
  192. Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene.
    J Clin Endocrinol Metab. 2008 Mar;93(3):792-800 PMID: 18000088
  193. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.
    Cancer Cell. 2006 Jun;9(6):425-34 PMID: 16766262
  194. RNA interference-mediated silencing of the acetyl-CoA-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells.
    Cancer Res. 2005 Aug 1;65(15):6719-25 PMID: 16061653
  195. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells.
    Cell Metab. 2005 Jul;2(1):21-33 PMID: 16054096
  196. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1.
    J Biol Chem. 2009 Mar 20;284(12):8023-32 PMID: 19150980
  197. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.
    Mol Cell. 2005 Apr 29;18(3):283-93 PMID: 15866171
  198. Osteogenic tumours in Lkb1-deficient mice.
    Exp Mol Pathol. 2008 Dec;85(3):223-6 PMID: 18761009
  199. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.
    Science. 2005 Dec 9;310(5754):1642-6 PMID: 16308421
  200. TOR signaling in growth and metabolism.
    Cell. 2006 Feb 10;124(3):471-84 PMID: 16469695
Article Info
Journal
Nature reviews. Cancer
Abbr.
Nat Rev Cancer
ISSN
1474-1768
DOI
10.1038/nrc2676
Published
2009-00-00
Pages
563-75
Language
English
Region
England
NLM ID
101124168
PMCID
PMC2756045
Subset
IM
Grants
NCI NIH HHS · T32 CA009370-26 · United States
NCI NIH HHS · P01 CA120964-030002 · United States
NIDDK NIH HHS · R01 DK080425 · United States
NCI NIH HHS · P01 CA120964 · United States
NCI NIH HHS · T32 CA009370 · United States
NIDDK NIH HHS · R01 DK080425-02 · United States
NIDDK NIH HHS · R01 DK080425-01 · United States
External Links
PubMed source DOI: 10.1038/nrc2676 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2