AMP-activated protein kinase and cancer
W. Wang
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA
Search for more papers by this authorK.-L. Guan
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA
Search for more papers by this authorW. Wang
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA
Search for more papers by this authorK.-L. Guan
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA
Search for more papers by this authorAbstract
AMP-activated protein kinase (AMPK) is a cellular energy sensor that is conserved in eukaryotes. Elevated AMP/ATP ratio activates AMPK, which inhibits energy-consuming processes and activates energy-producing processes to restore the energy homeostasis inside the cell. AMPK activators, metformin and thiazolidinediones, are used for the treatment of type II diabetes. Recently, reports have indicated that AMPK may also be a beneficial target for cancer treatment. Cancer cells have characteristic metabolic changes different from normal cells and, being a key metabolic regulator, AMPK may regulate the switch. AMPK may act to inhibit tumorigenesis through regulation of cell growth, cell proliferation, autophagy, stress responses and cell polarity.
References
- Andersson, U., Filipsson, K., Abbott, C.R., Woods, A., Smith, K., Bloom, S.R., Carling, D. & Small, C.J. 2004. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279, 12005–12008.
- Arad, M., Seidman, C.E. & Seidman, J.G. 2007. AMP-activated protein kinase in the heart: role during health and disease. Circ Res 100, 474–488.
- Baas, A.F., Boudeau, J., Sapkota, G.P., Smit, L., Medema, R., Morrice, N.A., Alessi, D.R. & Clevers, H.C. 2003. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J 22, 3062–3072.
- Besson, A., Assoian, R.K. & Roberts, J.M. 2004. Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors? Nat Rev Cancer 4, 948–955.
- Boudeau, J., Sapkota, G. & Alessi, D.R. 2003. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Lett 546, 159–165.
- Brugarolas, J. & Kaelin, W.G., Jr 2004. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6, 7–10.
- Brugarolas, J., Lei, K., Hurley, R.L., Manning, B.D., Reiling, J.H., Hafen, E., Witters, L.A., Ellisen, L.W. & Kaelin, W.G., Jr 2004. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18, 2893–2904.
- Brunelle, J.K., Bell, E.L., Quesada, N.M., Vercauteren, K., Tiranti, V., Zeviani, M., Scarpulla, R.C. & Chandel, N.S. 2005. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab 1, 409–414.
- Budanov, A.V. & Karin, M. 2008. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451–460.
- Budanov, A.V., Sablina, A.A., Feinstein, E., Koonin, E.V. & Chumakov, P.M. 2004. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304, 596–600.
- Carling, D., Zammit, V.A. & Hardie, D.G. 1987. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett 223, 217–222.
- Chu, I.M., Hengst, L. & Slingerland, J.M. 2008. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8, 253–267.
- Corradetti, M.N., Inoki, K. & Guan, K.L. 2005. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J Biol Chem 280, 9769–9772.
- Crighton, D., Wilkinson, S., O’Prey, J., Syed, N., Smith, P., Harrison, P.R., Gasco, M., Garrone, O., Crook, T. & Ryan, K.M. 2006. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121–134.
- Davies, S.P., Helps, N.R., Cohen, P.T. & Hardie, D.G. 1995. 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett 377, 421–425.
- DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G. & Thompson, C.B. 2008. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7, 11–20.
- Dekanty, A., Lavista-Llanos, S., Irisarri, M., Oldham, S. & Wappner, P. 2005. The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-alpha/Sima. J Cell Sci 118, 5431–5441.
- Dowling, R.J., Zakikhani, M., Fantus, I.G., Pollak, M. & Sonenberg, N. 2007. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67, 10804–10812.
- El-Mir, M.Y., Nogueira, V., Fontaine, E., Averet, N., Rigoulet, M. & Leverve, X. 2000. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275, 223–228.
- Emerling, B.M., Viollet, B., Tormos, K.V. & Chandel, N.S. 2007. Compound C inhibits hypoxic activation of HIF-1 independent of AMPK. FEBS Lett 581, 5727–5731.
- Evans, J.M., Donnelly, L.A., Emslie-Smith, A.M., Alessi, D.R. & Morris, A.D. 2005. Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304–1305.
- Feng, Z., Zhang, H., Levine, A.J. & Jin, S. 2005. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102, 8204–8209.
- Feng, Z., Hu, W., De Stanchina, E., Teresky, A.K., Jin, S., Lowe, S. & Levine, A.J. 2007. 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 67, 3043–3053.
- Giardiello, F.M., Welsh, S.B., Hamilton, S.R., Offerhaus, G.J., Gittelsohn, A.M., Booker, S.V., Krush, A.J., Yardley, J.H. & Luk, G.D. 1987. Increased risk of cancer in the Peutz–Jeghers syndrome. N Engl J Med 316, 1511–1514.
- Guldberg, P., Thor Straten, P., Ahrenkiel, V., Seremet, T., Kirkin, A.F. & Zeuthen, J. 1999. Somatic mutation of the Peutz–Jeghers syndrome gene, LKB1/STK11, in malignant melanoma. Oncogene 18, 1777–1780.
- Guzy, R.D., Hoyos, B., Robin, E., Chen, H., Liu, L., Mansfield, K.D., Simon, M.C., Hammerling, U. & Schumacker, P.T. 2005. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1, 401–408.
- Gwinn, D.M., Shackelford, D.B., Egan, D.F., Mihaylova, M.M., Mery, A., Vasquez, D.S., Turk, B.E. & Shaw, R.J. 2008. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30, 214–226.
- Hanahan, D. & Weinberg, R.A. 2000. The hallmarks of cancer. Cell 100, 57–70.
- Hardie, D.G. 2007. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8, 774–785.
- Hardie, D.G. 2008. Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett 582, 81–89.
- Hattori, Y., Nakano, Y., Hattori, S., Tomizawa, A., Inukai, K. & Kasai, K. 2008. High molecular weight adiponectin activates AMPK and suppresses cytokine-induced NF-kappaB activation in vascular endothelial cells. FEBS Lett 582, 1719–1724.
- Hawley, S.A., Boudeau, J., Reid, J.L., Mustard, K.J., Udd, L., Makela, T.P., Alessi, D.R. & Hardie, D.G. 2003. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2, 28.
- Hawley, S.A., Pan, D.A., Mustard, K.J., Ross, L., Bain, J., Edelman, A.M., Frenguelli, B.G. & Hardie, D.G. 2005. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2, 9–19.
- Hearle, N., Schumacher, V., Menko, F.H., Olschwang, S., Boardman, L.A., Gille, J.J., Keller, J.J., Westerman, A.M., Scott, R.J., Lim, W. et al. 2006. Frequency and spectrum of cancers in the Peutz–Jeghers syndrome. Clin Cancer Res 12, 3209–3215.
- Hemminki, A., Avizienyte, E., Roth, S., Loukola, A., Aaltonen, L.A., Jarvinen, H. & De La Chapelle, A. 1998. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Duodecim 114, 667–668.
- Huang, X., Wullschleger, S., Shpiro, N., McGuire, V.A., Sakamoto, K., Woods, Y.L., McBurnie, W., Fleming, S. & Alessi, D.R. 2008. Important role of the LKB1–AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 412, 211–221.
- Hudson, E.R., Pan, D.A., James, J., Lucocq, J.M., Hawley, S.A., Green, K.A., Baba, O., Terashima, T. & Hardie, D.G. 2003. A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr Biol 13, 861–866.
- Hurley, R.L., Anderson, K.A., Franzone, J.M., Kemp, B.E., Means, A.R. & Witters, L.A. 2005. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem 280, 29060–29066.
- 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-beta-d-ribofuranoside, in a human hepatocellular carcinoma cell line. Biochem Biophys Res Commun 287, 562–567.
- Inoki, K., Li, Y., Xu, T. & Guan, K.L. 2003a. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17, 1829–1834.
- Inoki, K., Zhu, T. & Guan, K.L. 2003b. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590.
- Iseli, T.J., Walter, M., Van Denderen, B.J., Katsis, F., Witters, L.A., Kemp, B.E., Michell, B.J. & Stapleton, D. 2005. AMP-activated protein kinase beta subunit tethers alpha and gamma subunits via its C-terminal sequence (186–270). J Biol Chem 280, 13395–13400.
- Jones, R.G., Plas, D.R., Kubek, S., Buzzai, M., Mu, J., Xu, Y., Birnbaum, M.J. & Thompson, C.B. 2005. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18, 283–293.
- Laderoute, K.R., Amin, K., Calaoagan, J.M., Knapp, M., Le, T., Orduna, J., Foretz, M. & Viollet, B. 2006. 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.
- Lee, M., Hwang, J.T., Lee, H.J., Jung, S.N., Kang, I., Chi, S.G., Kim, S.S. & Ha, J. 2003. AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. J Biol Chem 278, 39653–39661.
- Lee, C.H., Inoki, K., Karbowniczek, M., Petroulakis, E., Sonenberg, N., Henske, E.P. & Guan, K.L. 2007a. Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53. EMBO J 26, 4812–4823.
- Lee, J.H., Koh, H., Kim, M., Kim, Y., Lee, S.Y., Karess, R.E., Lee, S.H., Shong, M., Kim, J.M., Kim, J. & Chung, J. 2007b. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447, 1017–1020.
- Levine, A.J. 1997. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331.
- Levine, A.J., Momand, J. & Finlay, C.A. 1991. The p53 tumour suppressor gene. Nature 351, 453–456.
- Levine, A.J., Hu, W. & Feng, Z. 2006. The P53 pathway: what questions remain to be explored? Cell Death Differ 13, 1027–1036.
- Liang, J., Shao, S.H., Xu, Z.X., Hennessy, B., Ding, Z., Larrea, M., Kondo, S., Dumont, D.J., Gutterman, J.U., Walker, C.L., Slingerland, J.M. & Mills, G.B. 2007. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9, 218–224.
- Ljungman, M. 2000. Dial 9-1-1 for p53: mechanisms of p53 activation by cellular stress. Neoplasia 2, 208–225.
- Luptak, I., Shen, M., He, H., Hirshman, M.F., Musi, N., Goodyear, L.J., Yan, J., Wakimoto, H., Morita, H., Arad, M., Seidman, C.E., Seidman, J.G., Ingwall, J.S., Balschi, J.A. & Tian, R. 2007. Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage. J Clin Invest 117, 1432–1439.
- MacRae, C.A., Ghaisas, N., Kass, S., Donnelly, S., Basson, C.T., Watkins, H.C., Anan, R., Thierfelder, L.H., McGarry, K., Rowland, E., McKenna, W.J., Seidman, J.G. & Seidman, C.E. 1995. Familial Hypertrophic cardiomyopathy with Wolff–Pakinson–White syndrome maps to a locus on chromosome 7q3. J Clin Invest 96, 1216–1220.
- Mansfield, K.D., Guzy, R.D., Pan, Y., Young, R.M., Cash, T.P., Schumacker, P.T. & Simon, M.C. 2005. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 1, 393–399.
- Martin, S.G. & St Johnston, D. 2003. A role for Drosophila LKB1 in anterior–posterior axis formation and epithelial polarity. Nature 421, 379–384.
- Meijer, A.J. & Codogno, P. 2007. AMP-activated protein kinase and autophagy. Autophagy 3, 238–240.
- Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferre, P., Birnbaum, M.J., Stuck, B.J. & Kahn, B.B. 2004. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574.
- Mirouse, V., Swick, L.L., Kazgan, N., St Johnston, D. & Brenman, J.E. 2007. LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J Cell Biol 177, 387–392.
- Nagata, D., Mogi, M. & Walsh, K. 2003. AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress. J Biol Chem 278, 31000–31006.
- Nakau, M., Miyoshi, H., Seldin, M.F., Imamura, M., Oshima, M. & Taketo, M.M. 2002. Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Res 62, 4549–4553.
- Ouchi, N., Shibata, R. & Walsh, K. 2005. AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle. Circ Res 96, 838–846.
- Owen, M.R., Doran, E. & Halestrap, A.P. 2000. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348, 607–614.
- Papandreou, I., Lim, A.L., Laderoute, K. & Denko, N.C. 2008. Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ 15, 1572–1581.
- Pearson, H.B., McCarthy, A., Collins, C.M., Ashworth, A. & Clarke, A.R. 2008. Lkb1 deficiency causes prostate neoplasia in the mouse. Cancer Res 68, 2223–2232.
- Polekhina, G., Gupta, A., Michell, B.J., Van Denderen, B., Murthy, S., Feil, S.C., Jennings, I.G., Campbell, D.J., Witters, L.A., Parker, M.W., Kemp, B.E. & Stapleton, D. 2003. AMPK beta subunit targets metabolic stress sensing to glycogen. Curr Biol 13, 867–871.
- Reiling, J.H. & Hafen, E. 2004. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 18, 2879–2892.
- Renehan, A.G., Roberts, D.L. & Dive, C. 2008. Obesity and cancer: pathophysiological and biological mechanisms. Arch Physiol Biochem 114, 71–83.
- Rubinsztein, D.C., Gestwicki, J.E., Murphy, L.O. & Klionsky, D.J. 2007. Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6, 304–312.
- Sanchez-Cespedes, M., Parrella, P., Esteller, M., Nomoto, S., Trink, B., Engles, J.M., Westra, W.H., Herman, J.G. & Sidransky, D. 2002. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 62, 3659–3662.
- Sanders, M.J., Grondin, P.O., Hegarty, B.D., Snowden, M.A. & Carling, D. 2007. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 403, 139–148.
- Schmelzle, T. & Hall, M.N. 2000. TOR, a central controller of cell growth. Cell 103, 253–262.
- Scott, J.W., Hawley, S.A., Green, K.A., Anis, M., Stewart, G., Scullion, G.A., Norman, D.G. & Hardie, D.G. 2004. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest 113, 274–284.
- Semenza, G.L. 2003. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3, 721–732.
- Shaw, R.J. 2006. Glucose metabolism and cancer. Curr Opin Cell Biol 18, 598–608.
- Shaw, R.J., Kosmatka, M., Bardeesy, N., Hurley, R.L., Witters, L.A., DePinho, R.A. & Cantley, L.C. 2004. 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.
- Van Slegtenhorst, M., Nellist, M., Nagelkerken, B., Cheadle, J., Snell, R., Van Den Ouweland, A., Reuser, A., Sampson, J., Halley, D. & Van Der Sluijs, P. 1998. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 7, 1053–1057.
- Su, G.H., Hruban, R.H., Bansal, R.K., Bova, G.S., Tang, D.J., Shekher, M.C., Westerman, A.M., Entius, M.M., Goggins, M., Yeo, C.J. & Kern, S.E. 1999. Germline and somatic mutations of the STK11/LKB1 Peutz–Jeghers gene in pancreatic and biliary cancers. Am J Pathol 154, 1835–1840.
- Suter, M., Riek, U., Tuerk, R., Schlattner, U., Wallimann, T. & Neumann, D. 2006. Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem 281, 32207–32216.
- Takeda, H., Miyoshi, H., Kojima, Y., Oshima, M. & Taketo, M.M. 2006. Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/−p53−/− compound mutant mice. Oncogene 25, 1816–1820.
- Towler, M.C. & Hardie, D.G. 2007. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100, 328–341.
- Vogelstein, B., Lane, D. & Levine, A.J. 2000. Surfing the p53 network. Nature 408, 307–310.
- Warburg, O. 1956. On the origin of cancer cells. Science 123, 309–314.
- Williams, T. & Brenman, J.E. 2008. LKB1 and AMPK in cell polarity and division. Trends Cell Biol 18, 193–198.
- Woods, A., Johnstone, S.R., Dickerson, K., Leiper, F.C., Fryer, L.G., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M. & Carling, D. 2003. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13, 2004–2008.
- Woods, A., Dickerson, K., Heath, R., Hong, S.P., Momcilovic, M., Johnstone, S.R., Carlson, M. & Carling, D. 2005. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2, 21–33.
- Xiao, B., Heath, R., Saiu, P., Leiper, F.C., Leone, P., Jing, C., Walker, P.A., Haire, L., Eccleston, J.F., Davis, C.T., Martin, S.R., Carling, D. & Gamblin, S.J. 2007. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496–500.
- Ylikorkala, A., Rossi, D.J., Korsisaari, N., Luukko, K., Alitalo, K., Henkemeyer, M. & Makela, T.P. 2001. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science 293, 1323–1326.
- Young, J. & Povey, S. 1998. The genetic basis of tuberous sclerosis. Mol Med Today 4, 313–319.
- Young, L.H., Li, J., Baron, S.J. & Russell, R.R. 2005. AMP-activated protein kinase: a key stress signaling pathway in the heart. Trends Cardiovasc Med 15, 110–118.
- Zakikhani, M., Dowling, R., Fantus, I.G., Sonenberg, N. & Pollak, M. 2006. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66, 10269–10273.
- Zhang, L., Li, J., Young, L.H. & Caplan, M.J. 2006. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc Natl Acad Sci USA 103, 17272–17277.
- Zheng, B. & Cantley, L.C. 2007. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc Natl Acad Sci USA 104, 819–822.