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Metabolic roles of AMPK and metformin in cancer cells

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Molecules and Cells

Abstract

Metformin is one of the most widely used anti-diabetic agents in the world, and a growing body of evidence suggests that it may also be effective as an anti-cancer drug. Observational studies have shown that metformin reduces cancer incidence and cancer-related mortality in multiple types of cancer. These results have drawn attention to the mechanisms underlying metformin’s anti-cancer effects, which may include triggering of the AMP-activated protein kinase (AMPK) pathway, resulting in vulnerability to an energy crisis (leading to cell death under conditions of nutrient deprivation) and a reduction in circulating insulin/IGF-1 levels. Clinical trials are currently underway to determine the benefits, appropriate dosage, and tolerability of metformin in the context of cancer therapy. This review highlights fundamental aspects of the molecular mechanisms underlying metformin’s anti-cancer effects, describes the epidemiological evidence and ongoing clinical challenges, and proposes directions for future translational research.

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References

  • Alessi, D.R., Sakamoto, K., and Bayascas, J.R. (2006). LKB1-dependent signaling pathways. Ann. Rev. Biochem. 75, 137–163.

    Article  PubMed  CAS  Google Scholar 

  • Algire, C., Amrein, L., Zakikhani, M., Panasci, L., and Pollak, M. (2010). Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr. Relat. Cancer 17, 351–360.

    Article  PubMed  CAS  Google Scholar 

  • Algire, C., Amrein, L., Bazile, M., David, S., Zakikhani, M., and Pollak, M. (2011). Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene 30, 1174–1182.

    Article  PubMed  CAS  Google Scholar 

  • Appleyard, M.V., Murray, K.E., Coates, P.J., Wullschleger, S., Bray, S.E., Kernohan, N.M., Fleming, S., Alessi, D.R., and Thompson, A.M. (2012). Phenformin as prophylaxis and therapy in breast cancer xenografts. Br. J. Cancer 106, 1117–1122.

    Article  PubMed  CAS  Google Scholar 

  • Bailey, C.J., and Turner, R.C. (1996). Metformin. N. Engl. J. Med. 334, 574–579.

    Article  PubMed  CAS  Google Scholar 

  • Barger, J.F., and Plas, D.R. (2010). Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis. Endocr. Relat. Cancer 17, R287–304.

    Article  PubMed  CAS  Google Scholar 

  • Baur, D.M., Klotsche, J., Hamnvik, O.P., Sievers, C., Pieper, L., Wittchen, H.U., Stalla, G.K., Schmid, R.M., Kales, S.N., and Mantzoros, C.S. (2011). Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort. Metabolism 60, 1363–1371.

    Article  PubMed  CAS  Google Scholar 

  • Bodmer, M., Becker, C., Meier, C., Jick, S.S., and Meier, C.R. (2012). Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am. J. Gastroenterology 107, 620–626.

    Article  CAS  Google Scholar 

  • Bonanni, B., Puntoni, M., Cazzaniga, M., Pruneri, G., Serrano, D., Guerrieri-Gonzaga, A., Gennari, A., Trabacca, M.S., Galimberti, V., Veronesi, P., et al. (2012). Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J. Clin. Oncol. 30, 2593–2600.

    Article  PubMed  CAS  Google Scholar 

  • Bowker, S.L., Majumdar, S.R., Veugelers, P., and Johnson, J.A. (2006). Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29, 254–258.

    Article  PubMed  Google Scholar 

  • Buzzai, M., Jones, R.G., Amaravadi, R.K., Lum, J.J., DeBerardinis, R.J., Zhao, F., Viollet, B., and Thompson, C.B. (2007). Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745–6752.

    Article  PubMed  CAS  Google Scholar 

  • Campagnoli, C., Pasanisi, P., Abba, C., Ambroggio, S., Biglia, N., Brucato, T., Colombero, R., Danese, S., Donadio, M., Venturelli, E., et al. (2012). Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study. Clin. Breast Cancer 12, 175–182.

    Article  PubMed  CAS  Google Scholar 

  • Carling, D. (2004). The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem. Sci. 29, 18–24.

    Article  PubMed  CAS  Google Scholar 

  • Currie, C.J., Poole, C.D., and Gale, E.A. (2009). The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52, 1766–1777.

    Article  PubMed  CAS  Google Scholar 

  • Davies, S.P., Sim, A.T., and Hardie, D.G. (1990). Location and function of three sites phosphorylated on rat acetyl-CoA carboxylase by the AMP-activated protein kinase. Eur. J. Biochem. 187, 183–190.

    Article  PubMed  CAS  Google Scholar 

  • DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G., and Thompson, C.B. (2008). The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11–20.

    Article  PubMed  CAS  Google Scholar 

  • Dekanty, A., Lavista-Llanos, S., Irisarri, M., Oldham, S., and Wappner, P. (2005). The insulin-PI3K/TOR pathway induces a HIFdependent transcriptional response in Drosophila by promoting nuclear localization of HIF-alpha/Sima. J. Cell Sci. 118, 5431–5441.

    Article  PubMed  CAS  Google Scholar 

  • Donadon, V., Balbi, M., Mas, M.D., Casarin, P., and Zanette, G. (2010). Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int. 30, 750–758.

    Article  PubMed  CAS  Google Scholar 

  • Evans, J.M., Donnelly, L.A., Emslie-Smith, A.M., Alessi, D.R., and Morris, A.D. (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304–1305.

    Article  PubMed  Google Scholar 

  • Faubert, B., Boily, G., Izreig, S., Griss, T., Samborska, B., Dong, Z., Dupuy, F., Chambers, C., Fuerth, B.J., Viollet, B., et al. (2013). AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17, 113–124.

    Article  PubMed  CAS  Google Scholar 

  • Gill, R.K., Yang, S.H., Meerzaman, D., Mechanic, L.E., Bowman, E.D., Jeon, H.S., Roy Chowdhuri, S., Shakoori, A., Dracheva, T., Hong, K.M., et al. (2011). Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. Oncogene 30, 3784–3791.

    Article  PubMed  CAS  Google Scholar 

  • Giovannucci, E., Harlan, D.M., Archer, M.C., Bergenstal, R.M., Gapstur, S.M., Habel, L.A., Pollak, M., Regensteiner, J.G., and Yee, D. (2010). Diabetes and cancer: a consensus report. CA Cancer J. Clin. 60, 207–221.

    Article  PubMed  Google Scholar 

  • Gwinn, D.M., Shackelford, D.B., Egan, D.F., Mihaylova, M.M., Mery, A., Vasquez, D.S., Turk, B.E., and Shaw, R.J. (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226.

    Article  PubMed  CAS  Google Scholar 

  • Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G.C., Frederick, D.T., Hurley, A.D., Nellore, A., Kung, A.L., et al. (2013). Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 23, 302–315.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hassan, M.M., Curley, S.A., Li, D., Kaseb, A., Davila, M., Abdalla, E.K., Javle, M., Moghazy, D.M., Lozano, R.D., Abbruzzese, J.L., et al. (2010). Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 116, 1938–1946.

    Article  PubMed  Google Scholar 

  • Hirsch, H.A., Iliopoulos, D., Tsichlis, P.N., and Struhl, K. (2009). Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69, 7507–7511.

    Article  PubMed  CAS  Google Scholar 

  • Huang, X., Wullschleger, S., Shpiro, N., McGuire, V.A., Sakamoto, K., Woods, Y.L., McBurnie, W., Fleming, S., and Alessi, D.R. (2008). Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem. J. 412, 211–221.

    Article  PubMed  CAS  Google Scholar 

  • Jeon, S.M., Chandel, N.S., and Hay, N. (2012). AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665.

    Article  PubMed  CAS  Google Scholar 

  • Jiralerspong, S., Palla, S.L., Giordano, S.H., Meric-Bernstam, F., Liedtke, C., Barnett, C.M., Hsu, L., Hung, M.C., Hortobagyi, G.N., and Gonzalez-Angulo, A.M. (2009). Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J. Clin. Oncol. 27, 3297–3302.

    Article  PubMed  CAS  Google Scholar 

  • Larsson, O., Morita, M., Topisirovic, I., Alain, T., Blouin, M.J., Pollak, M., and Sonenberg, N. (2012). Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc. Natl. Acad. Sci. USA 109, 8977–8982.

    Article  PubMed  CAS  Google Scholar 

  • Lee, J.H., Kim, T.I., Jeon, S.M., Hong, S.P., Cheon, J.H., and Kim, W.H. (2012). The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int. J. Cancer 131, 752–759.

    Article  PubMed  CAS  Google Scholar 

  • LeRoith, D., Baserga, R., Helman, L., and Roberts, C.T., Jr. (1995). Insulin-like growth factors and cancer. Ann. Int. Med. 122, 54–59.

    Article  PubMed  CAS  Google Scholar 

  • Liu, L., Ulbrich, J., Muller, J., Wustefeld, T., Aeberhard, L., Kress, T.R., Muthalagu, N., Rycak, L., Rudalska, R., Moll, R., et al. (2012). Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 483, 608–612.

    Article  PubMed  CAS  Google Scholar 

  • Nattrass, M., and Alberti, K.G. (1978). Biguanides. Diabetologia 14, 71–74.

    Article  PubMed  CAS  Google Scholar 

  • Niehr, F., von Euw, E., Attar, N., Guo, D., Matsunaga, D., Sazegar, H., Ng, C., Glaspy, J.A., Recio, J.A., Lo, R.S., et al. (2011). Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J. Transl. Med. 9, 76.

    Article  PubMed  CAS  Google Scholar 

  • Ning, J., and Clemmons, D.R. (2010). AMP-activated protein kinase inhibits IGF-I signaling and protein synthesis in vascular smooth muscle cells via stimulation of insulin receptor substrate 1 S794 and tuberous sclerosis 2 S1345 phosphorylation. Mol. Endocrinol. 24, 1218–1229.

    Article  PubMed  CAS  Google Scholar 

  • Oliveras-Ferraros, C., Vazquez-Martin, A., and Menendez, J.A. (2009). Genome-wide inhibitory impact of the AMPK activator metformin on [kinesins, tubulins, histones, auroras and polo-like kinases] M-phase cell cycle genes in human breast cancer cells. Cell Cycle 8, 1633–1636.

    Article  PubMed  CAS  Google Scholar 

  • Owen, M.R., Doran, E., and 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.

    Article  PubMed  CAS  Google Scholar 

  • Pearce, E.L., Walsh, M.C., Cejas, P.J., Harms, G.M., Shen, H., Wang, L.S., Jones, R.G., and Choi, Y. (2009). Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107.

    Article  PubMed  CAS  Google Scholar 

  • Pollak, M. (2008). Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer 8, 915–928.

    Article  PubMed  CAS  Google Scholar 

  • Pollak, M.N. (2012). Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2, 778–790.

    Article  PubMed  CAS  Google Scholar 

  • Polyak, K., and Weinberg, R.A. (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9, 265–273.

    Article  PubMed  CAS  Google Scholar 

  • Rocha, G.Z., Dias, M.M., Ropelle, E.R., Osorio-Costa, F., Rossato, F.A., Vercesi, A.E., Saad, M.J., and Carvalheira, J.B. (2011). Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin. Cancer Res. 17, 3993–4005.

    Article  PubMed  CAS  Google Scholar 

  • Ron, D., and Walter, P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529.

    Article  PubMed  CAS  Google Scholar 

  • Rozengurt, E., Sinnett-Smith, J., and Kisfalvi, K. (2010). Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin. Cancer Res. 16, 2505–2511.

    Article  PubMed  CAS  Google Scholar 

  • Saito, S., Furuno, A., Sakurai, J., Sakamoto, A., Park, H.R., Shin-Ya, K., Tsuruo, T., and Tomida, A. (2009). Chemical genomics identifies the unfolded protein response as a target for selective cancer cell killing during glucose deprivation. Cancer Res. 69, 4225–4234.

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Cespedes, M. (2007). A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene 26, 7825–7832.

    Article  PubMed  CAS  Google Scholar 

  • Semenza, G.L. (2003). Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732.

    Article  PubMed  CAS  Google Scholar 

  • Shackelford, D.B., and Shaw, R.J. (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9, 563–575.

    Article  PubMed  CAS  Google Scholar 

  • Shackelford, D.B., Abt, E., Gerken, L., Vasquez, D.S., Seki, A., Leblanc, M., Wei, L., Fishbein, M.C., Czernin, J., Mischel, P.S., et al. (2013). LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143–158.

    Article  PubMed  CAS  Google Scholar 

  • Shu, Y., Sheardown, S.A., Brown, C., Owen, R.P., Zhang, S., Castro, R.A., Ianculescu, A.G., Yue, L., Lo, J.C., Burchard, E.G., et al. (2007). Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J. Clin. Invest. 117, 1422–1431.

    Article  PubMed  CAS  Google Scholar 

  • Solano, M.E., Sander, V., Wald, M.R., and Motta, A.B. (2008). Dehydroepiandrosterone and metformin regulate proliferation of murine T lymphocytes. Clin. Exp. Immunol. 153, 289–296.

    Article  PubMed  CAS  Google Scholar 

  • Vander Heiden, M.G., Cantley, L.C., and Thompson, C.B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033.

    Article  Google Scholar 

  • Vazquez-Martin, A., Oliveras-Ferraros, C., Cufi, S., Del Barco, S., Martin-Castillo, B., and Menendez, J.A. (2010). Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 9, 3807–3814.

    Article  PubMed  CAS  Google Scholar 

  • Vazquez-Martin, A., Oliveras-Ferraros, C., Cufi, S., Martin-Castillo, B., and Menendez, J.A. (2011). Metformin activates an ataxia telangiectasia mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle 10, 1499–1501.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Zakikhani, M., Dowling, R., Fantus, I.G., Sonenberg, N., and Pollak, M. (2006). Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66, 10269–10273.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Keun-Gyu Park.

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Choi, Y.K., Park, KG. Metabolic roles of AMPK and metformin in cancer cells. Mol Cells 36, 279–287 (2013). https://doi.org/10.1007/s10059-013-0169-8

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