The LKB1–AMPK pathway: metabolism and growth control in tumour suppression (original) (raw)

• Hong, S. P., Leiper, F. C., Woods, A., Carling, D. & Carlson, M. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc. Natl Acad. Sci. USA 100, 8839–8843 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Hawley, S. A. et al. Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).
  Article PubMed PubMed Central Google Scholar
• Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).
  Article CAS PubMed Google Scholar
• Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 391, 184–187 (1998).
  Article CAS PubMed Google Scholar
• Sanchez-Cespedes, M. et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62, 3659–3662 (2002).
  CAS PubMed Google Scholar
• Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007). This paper describes the phenotype that results from the combined mutation of oncogenic Kras and LKB1 inactivation in a well-studied mouse model of KRAS-dependent lung carcinogenesis. LKB1 showed the most dramatic phenotype of any tumour suppressor tested when it was combined with Kras mutation.
  Article CAS PubMed Google Scholar
• Wingo, S. N. et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS ONE 4, e5137 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Carling, D., Sanders, M. J. & Woods, A. The regulation of AMP-activated protein kinase by upstream kinases. Int. J. Obes. 32, S55–S59 (2008).
  Article CAS Google Scholar
• Lizcano, J. M. et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 23, 833–843 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Jaleel, M. et al. Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate. FEBS Lett. 579, 1417–1423 (2005).
  Article CAS PubMed Google Scholar
• Al-Hakim, A. K. et al. 14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK. J. Cell Sci. 118, 5661–5673 (2005).
  Article CAS PubMed Google Scholar
• Watts, J. L., Morton, D. G., Bestman, J. & Kemphues, K. J. The C. elegans par-4 gene encodes a putative serine–threonine kinase required for establishing embryonic asymmetry. Development 127, 1467–1475 (2000).
  CAS PubMed Google Scholar
• Anderson, K. A. et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7, 377–388 (2008).
  Article CAS PubMed Google Scholar
• Tamas, P. et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med. 203, 1665–1670 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Stahmann, N., Woods, A., Carling, D. & Heller, R. Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase-β. Mol. Cell. Biol. 26, 5933–5945 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Hawley, S. A. et al. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9–19 (2005).
  Article CAS PubMed Google Scholar
• Woods, A. et al. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21–33 (2005).
  Article CAS PubMed Google Scholar
• Hurley, R. L. et al. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 280, 29060–29066 (2005).
  Article CAS PubMed Google Scholar
• Hardie, D. G., Scott, J. W., Pan, D. A. & Hudson, E. R. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 546, 113–120 (2003).
  Article CAS PubMed Google Scholar
• Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).
  Article CAS PubMed Google Scholar
• Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006).
  Article CAS PubMed Google Scholar
• Holz, M. K., Ballif, B. A., Gygi, S. P. & Blenis, J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123, 569–80 (2005).
  Article CAS PubMed Google Scholar
• Choo, A. Y., Yoon, S. O., Kim, S. G., Roux, P. P. & Blenis, J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl Acad. Sci. USA 105, 17414–17419 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Thoreen, C. C. et al. An ATP-competitive mTOR inhibitor reveals rapamycin-insensitive functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Feldman, M. E. et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38 (2009).
  Article CAS PubMed Google Scholar
• Shaw, R. J. & Cantley, L. C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441, 424–430 (2006).
  Article CAS PubMed Google Scholar
• Huang, J. & Manning, B. D. The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 412, 179–190 (2008).
  Article CAS PubMed Google Scholar
• Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
  Article CAS PubMed Google Scholar
• Corradetti, M. N., Inoki, K., Bardeesy, N., DePinho, R. A. & Guan, K. L. 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 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Shaw, R. J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–99 (2004).
  Article CAS PubMed Google Scholar
• Liu, L. et al. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 21, 521–531 (2006).
  Article PubMed PubMed Central CAS Google Scholar
• Inoki, K. et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126, 955–968 (2006).
  Article CAS PubMed Google Scholar
• Hahn-Windgassen, A. et al. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J. Biol. Chem. 280, 32081–32089 (2005).
  Article CAS PubMed Google Scholar
• Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008). This study identified two highly conserved serines in the mTOR binding partner raptor as direct AMPK phosphorylation sites that are needed to inactivate mTORC1 signalling and promote cell cycle arrest.
  Article CAS PubMed PubMed Central Google Scholar
• Shackelford, D. B. et al. mTOR- and HIF-1α mediated tumor metabolism in an LKB1 mouse model of Peutz–Jeghers syndrome. Proc. Natl Acad. Sci. USA 18 Jun 2009 (doi:10.1073/pnas.0900465106).
• Carretero, J. et al. Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Oncogene 26, 1616–1625 (2007).
  Article CAS PubMed Google Scholar
• Karuman, P. et al. The Peutz–Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol. Cell 7, 1307–1319 (2001).
  Article CAS PubMed Google Scholar
• Tiainen, M., Vaahtomeri, K., Ylikorkala, A. & Makela, T. P. Growth arrest by the LKB1 tumor suppressor: induction of p21WAF1/CIP1. Hum. Mol. Genet. 11, 1497–1504 (2002).
  Article CAS PubMed Google Scholar
• Imamura, K., Ogura, T., Kishimoto, A., Kaminishi, M. & Esumi, H. 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, 562–567 (2001).
  Article CAS PubMed Google Scholar
• Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005).
  Article CAS PubMed Google Scholar
• Khanna, K. K. & Jackson, S. P. DNA double-strand breaks: signaling, repair and the cancer connection. Nature Genet. 27, 247–254 (2001).
  Article CAS PubMed Google Scholar
• Levine, A. J., Feng, Z., Mak, T. W., You, H. & Jin, S. Coordination and communication between the p53 and IGF-1–AKT–TOR signal transduction pathways. Genes Dev. 20, 267–275 (2006).
  Article CAS PubMed Google Scholar
• Budanov, A. V. & Karin, M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451–460 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Feng, Z. et al. The regulation of AMPK β1, 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. 67, 3043–3053 (2007).
  Article CAS PubMed Google Scholar
• Greer, E. L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107–30119 (2007).
  Article CAS PubMed Google Scholar
• Liang, J. et al. The energy sensing LKB1–AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. Nature Cell Biol. 9, 218–224 (2007).
  Article CAS PubMed Google Scholar
• Short, J. D. et al. AMP-activated protein kinase signaling results in cytoplasmic sequestration of p27. Cancer Res. 68, 6496–6506 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Baba, M. et al. 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. USA 103, 15552–15557 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, W. et al. AMP-activated protein kinase-regulated phosphorylation and acetylation of importin α1: involvement in the nuclear import of RNA-binding protein HuR. J. Biol. Chem. 279, 48376–48388 (2004).
  Article CAS PubMed Google Scholar
• Carling, D., Zammit, V. A. & Hardie, D. G. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 223, 217–222 (1987).
  Article CAS PubMed Google Scholar
• Sato, R., Goldstein, J. L. & Brown, M. S. 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. USA 90, 9261–9265 (1993).
  Article CAS PubMed PubMed Central Google Scholar
• Zhan, Y. et al. 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 (2008).
  Article CAS PubMed Google Scholar
• Chajes, V., Cambot, M., Moreau, K., Lenoir, G. M. & Joulin, V. Acetyl-CoA carboxylase α is essential to breast cancer cell survival. Cancer Res. 66, 5287–5294 (2006).
  Article CAS PubMed Google Scholar
• Brusselmans, K., De Schrijver, E., Verhoeven, G. & Swinnen, J. V. RNA interference-mediated silencing of the acetyl-CoA-carboxylase-a gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res. 65, 6719–6725 (2005).
  Article CAS PubMed Google Scholar
• Beckers, A. et al. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res. 67, 8180–8187 (2007).
  Article CAS PubMed Google Scholar
• Orita, H. et al. Selective inhibition of fatty acid synthase for lung cancer treatment. Clin. Cancer Res. 13, 7139–7145 (2007).
  CAS PubMed Google Scholar
• Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Rev. Cancer 7, 763–777 (2007).
  Article CAS PubMed Google Scholar
• Marsin, A. S. et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr. Biol. 10, 1247–1255 (2000).
  Article CAS PubMed Google Scholar
• Almeida, A., Moncada, S. & Bolanos, J. P. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nature Cell Biol. 6, 45–51 (2004).
  Article CAS PubMed Google Scholar
• Bando, H. et al. Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer. Clin. Cancer Res. 11, 5784–5792 (2005).
  Article CAS PubMed Google Scholar
• Telang, S. et al. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 25, 7225–7234 (2006).
  Article CAS PubMed Google Scholar
• Clem, B. et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol. Cancer Ther 7, 110–120 (2008).
  Article CAS PubMed Google Scholar
• Yang, W. et al. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J. Biol. Chem. 276, 38341–38344 (2001).
  Article CAS PubMed Google Scholar
• Berdeaux, R. et al. SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nature Med. 13, 597–603 (2007).
  Article CAS PubMed Google Scholar
• Dequiedt, F. et al. New role for hPar-1 kinases EMK and C-TAK1 in regulating localization and activity of class IIa histone deacetylases. Mol. Cell. Biol. 26, 7086–7102 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• McGee, S. L. et al. AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes 57, 860–867 (2008).
  Article CAS PubMed Google Scholar
• Koo, S. H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005).
  Article CAS PubMed Google Scholar
• Screaton, R. A. et al. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119, 61–74 (2004).
  Article CAS PubMed Google Scholar
• Jansson, D. et al. Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2. Proc. Natl Acad. Sci. USA 105, 10161–10166 (2008).
  Article PubMed PubMed Central Google Scholar
• Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005). Using tissue-specific inactivation of LKB1 in mice, this study showed that LKB1-dependent signals are required in the liver for the widely used type 2 diabetes drug metformin to lower blood glucose.
  Article CAS PubMed PubMed Central Google Scholar
• Fu, A. & Screaton, R. A. Using kinomics to delineate signaling pathways: control of CRTC2/TORC2 by the AMPK family. Cell Cycle 7, 3823–3828 (2008).
  Article CAS PubMed Google Scholar
• Wu, L. et al. Transforming activity of MECT1–MAML2 fusion oncoprotein is mediated by constitutive CREB activation. EMBO J. 24, 2391–2402 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Canettieri, G. et al. The coactivator CRTC1 promotes cell proliferation and transformation via AP-1. Proc. Natl Acad. Sci. USA 106, 1445–1450 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).
  Article PubMed CAS PubMed Central Google Scholar
• Brooks, C. L. & Gu, W. How does SIRT1 affect metabolism, senescence and cancer? Nature Rev. Cancer 9, 123–128 (2009).
  Article CAS Google Scholar
• Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).
  Article CAS PubMed Google Scholar
• Shaw, R. J. Glucose metabolism and cancer. Curr. Opin. Cell Biol. 18, 598–608 (2006).
  Article CAS PubMed Google Scholar
• Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Rev. Cancer 8, 705–713 (2008).
  Article CAS Google Scholar
• Semenza, G. L. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J. Bioenerg. Biomembr. 39, 231–234 (2007).
  Article CAS PubMed Google Scholar
• Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Med. 10, 594–601 (2004).
  Article CAS PubMed Google Scholar
• Fantin, V. R., St-Pierre, J. & Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434 (2006).
  Article CAS PubMed Google Scholar
• Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Martin, S. G. & St Johnston, D. A role for Drosophila LKB1 in anterior–posterior axis formation and epithelial polarity. Nature 421, 379–384 (2003).
  Article CAS PubMed Google Scholar
• Mirouse, V., Swick, L. L., Kazgan, N., St Johnston, D. & Brenman, J. E. LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J. Cell Biol. 177, 387–392 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, J. H. et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447, 1017–1020 (2007).
  Article CAS PubMed Google Scholar
• Tomancak, P. et al. A Drosophila melanogaster homologue of Caenorhabditis elegans par-1 acts at an early step in embryonic-axis formation. Nature Cell Biol. 2, 458–460 (2000).
  Article CAS PubMed Google Scholar
• Shulman, J. M., Benton, R. & St Johnston, D. The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Cell 101, 377–388 (2000).
  Article CAS PubMed Google Scholar
• Baas, A. F. et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116, 457–466 (2004). This study was the first to show a key role for mammalian LKB1 in establishing cell polarity, even in cells that lack cell–cell contacts.
  Article CAS PubMed Google Scholar
• Shelly, M., Cancedda, L., Heilshorn, S., Sumbre, G. & Poo, M. M. LKB1/STRAD promotes axon initiation during neuronal polarization. Cell 129, 565–577 (2007).
  Article CAS PubMed Google Scholar
• Barnes, A. P. et al. LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons. Cell 129, 549–563 (2007). References 93 and 94 show that LKB1 and its downstream SAD kinases play crucial parts in polarity and axonogenesis in the developing mammalian brain.
  Article CAS PubMed Google Scholar
• Hezel, A. F. & Bardeesy, N. LKB1; linking cell structure and tumor suppression. Oncogene 27, 6908–6919 (2008).
  Article CAS PubMed Google Scholar
• Kojima, Y. et al. Suppression of tubulin polymerization by the LKB1-microtubule-associated protein/microtubule affinity-regulating kinase signaling. J. Biol. Chem. 282, 23532–23540 (2007).
  Article CAS PubMed Google Scholar
• Biernat, J. et al. Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. Mol. Biol. Cell 13, 4013–4028 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Sun, T. Q. et al. PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling. Nature Cell Biol. 3, 628–636 (2001).
  Article CAS PubMed Google Scholar
• Ossipova, O., Dhawan, S., Sokol, S. & Green, J. B. Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development. Dev. Cell 8, 829–841 (2005).
  Article CAS PubMed Google Scholar
• Elbert, M., Cohen, D. & Musch, A. PAR1b promotes cell–cell adhesion and inhibits Dishevelled-mediated transformation of Madin-Darby canine kidney cells. Mol. Biol. Cell 17, 3345–3355 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Schlessinger, K., McManus, E. J. & Hall, A. Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity. J. Cell Biol. 178, 355–361 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, X. et al. Dishevelled promotes axon differentiation by regulating atypical protein kinase C. Nature Cell Biol. 9, 743–754 (2007).
  Article CAS PubMed Google Scholar
• Narimatsu, M. et al. Regulation of planar cell polarity by Smurf ubiquitin ligases. Cell 137, 295–307 (2009).
  Article CAS PubMed Google Scholar
• Zhang, L., Li, J., Young, L. H. & Caplan, M. J. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc. Natl Acad. Sci. USA 103, 17272–17277 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Zheng, B. & Cantley, L. C. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc. Natl Acad. Sci. USA 104, 819–822 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Sebbagh, M., Santoni, M. J., Hall, B., Borg, J. P. & Schwartz, M. A. Regulation of LKB1/STRAD localization and function by E-cadherin. Curr. Biol. 19, 37–42 (2009).
  Article CAS PubMed Google Scholar
• Horman, S. et al. AMP-activated protein kinase phosphorylates and desensitizes smooth muscle myosin light chain kinase. J. Biol. Chem. 283, 18505–18512 (2008).
  Article CAS PubMed Google Scholar
• Yamamoto, H. et al. Identification of a novel substrate for TNFα-induced kinase NUAK2. Biochem. Biophys. Res. Commun. 365, 541–547 (2008).
  Article CAS PubMed Google Scholar
• ten Klooster, J. P. et al. Mst4 and Ezrin induce brush borders downstream of the Lkb1/Strad/Mo25 polarization complex. Dev. Cell 16, 551–562 (2009).
  Article CAS PubMed Google Scholar
• Partanen, J. I., Nieminen, A. I., Makela, T. P. & Klefstrom, J. Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization. Proc. Natl Acad. Sci. USA 104, 14694–14699 (2007).
  Article PubMed CAS PubMed Central Google Scholar
• Aranda, V. et al. Par6–aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nature Cell Biol. 8, 1235–1245 (2006).
  Article CAS PubMed Google Scholar
• Dow, L. E. et al. The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge. Oncogene 26, 2272–2282 (2007).
  Article CAS PubMed Google Scholar
• Nolan, M. E. et al. The polarity protein Par6 induces cell proliferation and is overexpressed in breast cancer. Cancer Res. 68, 8201–8209 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ylikorkala, A. et al. Vascular abnormalities and deregulation of VEGF in _Lkb1_-deficient mice. Science 293, 1323–1326 (2001).
  Article CAS PubMed Google Scholar
• Bardeesy, N. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002).
  Article CAS PubMed Google Scholar
• Miyoshi, H. et al. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 62, 2261–2266 (2002).
  CAS PubMed Google Scholar
• Jishage, K. et al. Role of Lkb1, the causative gene of Peutz–Jegher's syndrome, in embryogenesis and polyposis. Proc. Natl Acad. Sci. USA 99, 8903–8908 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Rossi, D. J. et al. Induction of cyclooxygenase-2 in a mouse model of Peutz–Jeghers polyposis. Proc. Natl Acad. Sci. USA 99, 12327–12332 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Katajisto, P. et al. LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Nature Genet. 40, 455–459 (2008).
  Article CAS PubMed Google Scholar
• Vaahtomeri, K. et al. Lkb1 is required for TGFβ-mediated myofibroblast differentiation. J. Cell Sci. 121, 3531–3540 (2008).
  Article CAS PubMed Google Scholar
• Contreras, C. M. et al. Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas. Cancer Res. 68, 759–766 (2008).
  Article CAS PubMed Google Scholar
• Carretero, J., Medina, P. P., Pio, R., Montuenga, L. M. & Sanchez-Cespedes, M. Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene. Oncogene 23, 5084–5091 (2004).
  Article PubMed CAS Google Scholar
• Makowski, L. & Hayes, D. N. Role of LKB1 in lung cancer development. Br. J. Cancer 99, 683–688 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Gurumurthy, S., Hezel, A. F., Berger, J. H., Bosenberg, M. W. & Bardeesy, N. LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis. Cancer Res. 68, 55–63 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hardie, D. G. AMP-activated protein kinase as a drug target. Annu. Rev. Pharmacol. Toxicol. 47, 185–210 (2007).
  Article CAS PubMed Google Scholar
• Hundal, R. S. et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49, 2063–2069 (2000).
  Article CAS PubMed Google Scholar
• Hardie, D. G. Neither LKB1 nor AMPK are the direct targets of metformin. Gastroenterology 131, 973 (2006).
  Article PubMed Google Scholar
• Legro, R. S. et al. Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J. Clin. Endocrinol. Metab. 93, 792–800 (2008).
  Article CAS PubMed Google Scholar
• Shu, Y. et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J. Clin. Invest. 117, 1422–1431 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Schneider, M. B. et al. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 120, 1263–1270 (2001).
  Article CAS PubMed Google Scholar
• Anisimov, V. N. et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp. Gerontol. 40, 685–693 (2005).
  Article CAS PubMed Google Scholar
• Zakikhani, M., Dowling, R., Fantus, I. G., Sonenberg, N. & Pollak, M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66, 10269–10273 (2006).
  Article CAS PubMed Google Scholar
• Zakikhani, M., Dowling, R. J., Sonenberg, N. & Pollak, M. N. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev. Res. 1, 369–375 (2008).
  Article CAS Google Scholar
• Swinnen, J. V. et al. Mimicry of a cellular low energy status blocks tumor cell anabolism and suppresses the malignant phenotype. Cancer Res. 65, 2441–2448 (2005).
  Article CAS PubMed Google Scholar
• Buzzai, M. et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745–6752 (2007). Following up these authors' previous finding that AMPK can activate a p53-dependent checkpoint, this study shows that metformin and AICAR have p53-dependent anti-tumour effects in xenografts.
  Article CAS PubMed Google Scholar
• Algire, C., Zakikhani, M., Blouin, M. J., Shuai, J. H. & Pollak, M. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr. Relat. Cancer 15, 833–839 (2008).
  Article CAS PubMed Google Scholar
• Huang, X. et al. Important role of the LKB1–AMPK pathway in suppressing tumorigenesis in _PTEN_-deficient mice. Biochem. J. 412, 211–221 (2008). This is the first study to directly examine the ability of metformin, phenformin and the targeted small molecule A769662, which activates AMPK, to suppress cancer in a spontaneously arising genetic mouse model.
  Article CAS PubMed Google Scholar
• Dykens, J. A. et al. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol. Appl. Pharmacol. 233, 203–210 (2008).
  Article CAS PubMed Google Scholar
• Owen, M. R., Doran, E. & Halestrap, A. P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607–614 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Scott, J. W. et al. Thienopyridone drugs are selective activators of AMP-activated protein kinase β1-containing complexes. Chem. Biol. 15, 1220–1230 (2008).
  Article CAS PubMed Google Scholar
• Cool, B. et al. 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 (2006).
  Article CAS PubMed Google Scholar
• Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. & Morris, A. D. Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304–1305 (2005).
  Article PubMed PubMed Central Google Scholar
• Bowker, S. L., Majumdar, S. R., Veugelers, P. & Johnson, J. A. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29, 254–258 (2006).
  Article PubMed Google Scholar
• Jiralerspong, S. et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J. Clin. Oncol. 1 Jun 2009 (doi: 10.1200/JCO.2009.19.6410).
• Goodwin, P. J., Ligibel, J. A. & Stambolic, V. Metformin in breast cancer: time for action. J. Clin. Oncol. 1 Jun 2009 (doi: 10.1200/JCO.2009.22.1630).
• Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nature Rev. Cancer 8, 915–928 (2008).
  Article CAS Google Scholar
• Erdemoglu, E., Guney, M., Giray, S. G., Take, G. & Mungan, T. Effects of metformin on mammalian target of rapamycin in a mouse model of endometrial hyperplasia. Eur. J. Obstet. Gynecol. Reprod. Biol. 4 Jun 2009 (doi:10.1016/j.ejogrb.2009.04.034).
• Memmott, R. M. et al. Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non-small cell lung cancer cells. Cancer Res. 68, 580–588 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Nafz, J. et al. Interference with energy metabolism by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside induces HPV suppression in cervical carcinoma cells and apoptosis in the absence of LKB1. Biochem. J. 403, 501–510 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Buzzai, M. et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidation. Oncogene 21, 4165–4173 (2005).
  Article CAS Google Scholar
• Shell, S. A. et al. Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle 7, 1769–1775 (2008).
  Article CAS PubMed Google Scholar
• Laderoute, K. R. et al. 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol. Cell. Biol. 26, 5336–5347 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• O'Connor, M. J., Martin, N. M. & Smith, G. C. Targeted cancer therapies based on the inhibition of DNA strand break repair. Oncogene 26, 7816–7824 (2007).
  Article CAS PubMed Google Scholar
• Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc. Natl Acad. Sci. USA 98, 10320–10325 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Johannessen, C. M. et al. TORC1 is essential for NF1-associated malignancies. Curr. Biol. 18, 56–62 (2008).
  Article CAS PubMed Google Scholar
• Lee, L. et al. Efficacy of a rapamycin analog (CCI-779) and IFN-γ in tuberous sclerosis mouse models. Genes Chromosom. Cancer 42, 213–227 (2005).
  Article CAS PubMed Google Scholar
• Wei, C. et al. Suppression of Peutz–Jeghers polyposis by targeting mammalian target of rapamycin signaling. Clin. Cancer Res. 14, 1167–1171 (2008).
  Article CAS PubMed Google Scholar
• Robinson, J. et al. Oral rapamycin reduces tumour burden and vascularization in Lkb1+/− mice. J. Pathol. 31 Mar 2009 (doi: 10.1002/path.2562).
• Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).
  Article CAS PubMed Google Scholar
• Cloughesy, T. F. et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent _PTEN_-deficient glioblastoma. PLoS Med. 5, e8 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Bissler, J. J. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med. 358, 140–151 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Davies, D. M. et al. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N. Engl. J. Med. 358, 200–203 (2008).
  Article CAS PubMed Google Scholar
• Martinez, M. E., Marshall, J. R. & Giovannucci, E. Diet and cancer prevention: the roles of observation and experimentation. Nature Rev. Cancer 8, 694–703 (2008).
  Article CAS Google Scholar
• McTiernan, A. Mechanisms linking physical activity with cancer. Nature Rev. Cancer 8, 205–211 (2008).
  Article CAS Google Scholar
• Jiang, W., Zhu, Z. & Thompson, H. J. 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. 68, 5492–5499 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Moore, T. et al. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev. Res. 1, 65–76 (2008).
  Article CAS Google Scholar
• Kelesidis, I., Kelesidis, T. & Mantzoros, C. S. Adiponectin and cancer: a systematic review. Br. J. Cancer 94, 1221–1225 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Vona-Davis, L., Howard-McNatt, M. & Rose, D. P. Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. Obes. Rev. 8, 395–408 (2007).
  Article CAS PubMed Google Scholar
• Sugiyama, M. et al. Adiponectin inhibits colorectal cancer cell growth through the AMPK/mTOR pathway. Int. J. Oncol. 34, 339–344 (2009).
  CAS PubMed Google Scholar
• Zheng, B. et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol. Cell 33, 237–247 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hallstrom, T. C., Mori, S. & Nevins, J. R. An E2F1-dependent gene expression program that determines the balance between proliferation and cell death. Cancer Cell 13, 11–22 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, M. & Vasioukhin, V. Cell polarity and cancer--cell and tissue polarity as a non-canonical tumor suppressor. J. Cell Sci. 121, 1141–1150 (2008).
  Article CAS PubMed Google Scholar
• Saadat, I. et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447, 330–333 (2007).
  Article CAS PubMed Google Scholar
• Hoyer-Hansen, M. & Jaattela, M. AMP-activated protein kinase: a universal regulator of autophagy? Autophagy 3, 381–383 (2007).
  Article PubMed Google Scholar
• Wang, W., Yang, X., Lopez de Silanes, I., Carling, D. & Gorospe, M. Increased AMP:ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function. J. Biol. Chem. 278, 27016–27023 (2003).
  Article CAS PubMed Google Scholar
• Brugarolas, J. & Kaelin, W. G., Jr. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6, 7–10 (2004).
  Article CAS PubMed Google Scholar
• Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R. & Kaelin, W. G. Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4, 147–158 (2003).
  Article CAS PubMed Google Scholar
• Hurov, J. B., Watkins, J. L. & Piwnica-Worms, H. Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Curr. Biol. 14, 736–741 (2004).
  Article CAS PubMed Google Scholar
• Suzuki, A. et al. aPKC acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity. Curr. Biol. 14, 1425–1435 (2004).
  Article CAS PubMed Google Scholar
• Kusakabe, M. & Nishida, E. The polarity-inducing kinase Par-1 controls Xenopus gastrulation in cooperation with 14-3-3 and aPKC. EMBO J. 23, 4190–4201 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Y. et al. PAR-1 kinase phosphorylates Dlg and regulates its postsynaptic targeting at the Drosophila neuromuscular junction. Neuron 53, 201–215 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Benton, R. & St Johnston, D. Drosophila PAR-1 and 14-3-3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells. Cell 115, 691–704 (2003).
  Article CAS PubMed Google Scholar
• Ossipova, O., Bardeesy, N., DePinho, R. A. & Green, J. B. LKB1 (XEEK1) regulates Wnt signalling in vertebrate development. Nature Cell Biol. 5, 889–894 (2003).
  Article CAS PubMed Google Scholar
• Asada, N., Sanada, K. & Fukada, Y. LKB1 regulates neuronal migration and neuronal differentiation in the developing neocortex through centrosomal positioning. J. Neurosci 27, 11769–11775 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, S. et al. The tumor suppressor LKB1 regulates lung cancer cell polarity by mediating cdc42 recruitment and activity. Cancer Res. 68, 740–748 (2008).
  Article CAS PubMed Google Scholar
• Alessi, D. R., Sakamoto, K. & Bayascas, J. R. Lkb1-dependent signaling pathways. Annu. Rev. Biochem. 75, 137–163 (2006).
  Article CAS PubMed Google Scholar
• Puffenberger, E. G. et al. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. Brain 130, 1929–1941 (2007).
  Article PubMed Google Scholar
• Towler, M. C. et al. A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis. Biochem. J. 416, 1–14 (2008).
  Article CAS PubMed Google Scholar
• Denison, F. C., Hiscock, N. J., Carling, D. & Woods, A. Characterization of an alternative splice variant of LKB1. J. Biol. Chem. 284, 67–76 (2009).
  Article CAS PubMed Google Scholar
• Marignani, P. A. et al. Novel splice isoforms of STRADα differentially affect LKB1 activity, complex assembly and subcellular localization. Cancer Biol. Ther. 6, 1627–1631 (2007).
  Article CAS PubMed Google Scholar
• McBride, A., Ghilagaber, S., Nikolaev, A. & Hardie, D. G. The glycogen-binding domain on the AMPK β subunit allows the kinase to act as a glycogen sensor. Cell Metab. 9, 23–34 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Xiao, B. et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496–500 (2007).
  Article CAS PubMed Google Scholar
• Sanders, M. J., Grondin, P. O., Hegarty, B. D., Snowden, M. A. & Carling, D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem. J. 403, 139–148 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Dolinsky, V. W. & Dyck, J. R. Role of AMP-activated protein kinase in healthy and diseased hearts. Am. J. Physiol. Heart Circ. Physiol. 291, H2557–H2569 (2006).
  Article CAS PubMed Google Scholar
• Robinson, J., Nye, E., Stamp, G. & Silver, A. Osteogenic tumours in _Lkb1_-deficient mice. Exp. Mol. Pathol. 85, 223–226 (2008).
  Article CAS PubMed Google Scholar
• Takeda, H., Miyoshi, H., Kojima, Y., Oshima, M. & Taketo, M. M. Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1 +/− _p53_−/− compound mutant mice. Oncogene 25, 1816–1820 (2006).
  Article CAS PubMed Google Scholar
• Wei, C. et al. Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. Cancer Res. 65, 11297–11303 (2005).
  Article CAS PubMed Google Scholar
• Shorning, B. Y. et al. Lkb1 deficiency alters goblet and paneth cell differentiation in the small intestine. PLoS ONE 4, e4264 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Pearson, H. B., McCarthy, A., Collins, C. M., Ashworth, A. & Clarke, A. R. Lkb1 deficiency causes prostate neoplasia in the mouse. Cancer Res. 68, 2223–2232 (2008).
  Article CAS PubMed Google Scholar
• Hezel, A. F. et al. Pancreatic LKB1 deletion leads to acinar polarity defects and cystic neoplasms. Mol. Cell. Biol. 28, 2414–2425 (2008).
  Article CAS PubMed PubMed Central Google Scholar