Skip to main content
SpringerLink
Log in

The double-edged sword of AMPK signaling in cancer and its therapeutic implications

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

5′-AMP-activated protein kinase (AMPK) plays a pivotal role in maintaining energy and redox homeostasis under various metabolic stress conditions. Metabolic adaptation, which can be triggered by the activation of AMPK during metabolic stress, is the critical process for cell survival through the maintenance of ATP and NADPH levels. The importance of such regulation of fundamental process poses the AMPK signaling pathway in one of the most attractive therapeutic targets in many pathologies such as diabetes and cancer. In cancer, however, accumulating data suggest that the role of AMPK would not be simply defined as anti- or pro-tumorigenic, but it seems to have two faces like a double-edged sword. Importantly, recent studies showed that the anti-tumorigenic effects of many ‘indirect’ AMPK activators such as anti-diabetic biguanides are not dependent on AMPK; rather the activation of AMPK induces the resistance to their cytotoxic effects, emphasizing the pro-tumorigenic effect of AMPK. In this review, we summarize and discuss recent findings suggesting the two faces of AMPK in cancer, and discuss how we can exploit this unique feature of AMPK for novel therapeutic intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Auciello, F.R., F.A. Ross, N. Ikematsu, and D.G. Hardie. 2014. Oxidative stress activates AMPK in cultured cells primarily by increasing cellular AMP and/or ADP. FEBS Letters 588: 3361–3366.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bardeesy, N., M. Sinha, A.F. Hezel, S. Signoretti, N.A. Hathaway, N.E. Sharpless, M. Loda, D.R. Carrasco, and R.A. Depinho. 2002. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419: 162–167.

    Article  CAS  PubMed  Google Scholar 

  • Borgdorff, V., U. Rix, G.E. Winter, M. Gridling, A.C. Muller, F.P. Breitwieser, C. Wagner, J. Colinge, K.L. Bennett, G. Superti-Furga, and S.N. Wagner. 2014. A chemical biology approach identifies AMPK as a modulator of melanoma oncogene MITF. Oncogene 33: 2531–2539.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Cardaci, S., G. Filomeni, and M.R. Ciriolo. 2012. Redox implications of AMPK-mediated signal transduction beyond energetic clues. Journal of Cell Science 125: 2115–2125.

    Article  CAS  PubMed  Google Scholar 

  • Carling, D., V.A. Zammit, and D.G. Hardie. 1987. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Letters 223: 217–222.

    Article  CAS  PubMed  Google Scholar 

  • Carretero, J., T. Shimamura, K. Rikova, A.L. Jackson, M.D. Wilkerson, C.L. Borgman, M.S. Buttarazzi, B.A. Sanofsky, K.L. Mcnamara, K.A. Brandstetter, Z.E. Walton, T.L. Gu, J.C. Silva, K. Crosby, G.I. Shapiro, S.M. Maira, H. Ji, D.H. Castrillon, C.F. Kim, C. Garcia-Echeverria, N. Bardeesy, N.E. Sharpless, N.D. Hayes, W.Y. Kim, J.A. Engelman, and K.K. Wong. 2010. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell 17: 547–559.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cheng, H., P. Liu, F. Zhang, E. Xu, L. Symonds, C.E. Ohlson, R.T. Bronson, S.M. Maira, E. Di Tomaso, J. Li, A.P. Myers, L.C. Cantley, G.B. Mills, and J.J. Zhao. 2014. A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition. Cancer Research 74: 15–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Choi, S.L., S.J. Kim, K.T. Lee, J. Kim, J. Mu, M.J. Birnbaum, S. Soo Kim, and J. Ha. 2001. The regulation of AMP-activated protein kinase by H(2)O(2). Biochemical and biophysical research communications 287: 92–97.

    Article  CAS  PubMed  Google Scholar 

  • Contreras, C.M., E.A. Akbay, T.D. Gallardo, J.M. Haynie, S. Sharma, O. Tagao, N. Bardeesy, M. Takahashi, J. Settleman, K.K. Wong, and D.H. Castrillon. 2010. Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy. Disease models & mechanisms 3: 181–193.

    Article  CAS  Google Scholar 

  • Contreras, C.M., S. Gurumurthy, J.M. Haynie, L.J. Shirley, E.A. Akbay, S.N. Wingo, J.O. Schorge, R.R. Broaddus, K.K. Wong, N. Bardeesy, and D.H. Castrillon. 2008. Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas. Cancer Research 68: 759–766.

    Article  CAS  PubMed  Google Scholar 

  • Corradetti, M.N., K. Inoki, N. Bardeesy, R.A. Depinho, and K.L. Guan. 2004. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes & Development 18: 1533–1538.

    Article  CAS  Google Scholar 

  • Davies, S.P., N.R. Helps, P.T. Cohen, and D.G. Hardie. 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 Letters 377: 421–425.

    Article  CAS  PubMed  Google Scholar 

  • Decensi, A., M. Puntoni, P. Goodwin, M. Cazzaniga, A. Gennari, B. Bonanni, and S. Gandini. 2010. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer prevention research 3: 1451–1461.

    Article  CAS  PubMed  Google Scholar 

  • Dupuy, F., T. Griss, J. Blagih, G. Bridon, D. Avizonis, C. Ling, Z. Dong, D.R. Siwak, M.G. Annis, G.B. Mills, W.J. Muller, P.M. Siegel, and R.G. Jones. 2013. LKB1 is a central regulator of tumor initiation and pro-growth metabolism in ErbB2-mediated breast cancer. Cancer & metabolism 1: 18.

    Article  Google Scholar 

  • El-Masry, O.S., B.L. Brown, and P.R. Dobson. 2012. Effects of activation of AMPK on human breast cancer cell lines with different genetic backgrounds. Oncology letters 3: 224–228.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Emerling, B.M., F. Weinberg, C. Snyder, Z. Burgess, G.M. Mutlu, B. Viollet, G.R. Budinger, and N.S. Chandel. 2009. Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio. Free Radical Biology and Medicine 46: 1386–1391.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  • Faubert, B., G. Boily, S. Izreig, T. Griss, B. Samborska, Z. Dong, F. Dupuy, C. Chambers, B.J. Fuerth, B. Viollet, O.A. Mamer, D. Avizonis, R.J. Deberardinis, P.M. Siegel, and R.G. Jones. 2013. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metabolism 17: 113–124.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Faubert, B., E.E. Vincent, T. Griss, B. Samborska, S. Izreig, R.U. Svensson, O.A. Mamer, D. Avizonis, D.B. Shackelford, R.J. Shaw, and R.G. Jones. 2014a. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1alpha. Proceedings of the National Academy of Sciences of the United States of America 111: 2554–2559.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Faubert, B., E.E. Vincent, M.C. Poffenberger, and R.G. Jones, 2014b. The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator. Cancer letters 356(2): 165–70. doi:10.1016/j.canlet.2014.01.018.

  • Fernandez, M.R., M.D. Henry, and R.E. Lewis. 2012. Kinase suppressor of Ras 2 (KSR2) regulates tumor cell transformation via AMPK. Molecular and Cellular Biology 32: 3718–3731.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Frigo, D.E., M.K. Howe, B.M. Wittmann, A.M. Brunner, I. Cushman, Q. Wang, M. Brown, A.R. Means, and D.P. Mcdonnell. 2011. CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells. Cancer Research 71: 528–537.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fung, C., R. Lock, S. Gao, E. Salas, and J. Debnath. 2008. Induction of autophagy during extracellular matrix detachment promotes cell survival. Molecular Biology of the Cell 19: 797–806.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Godlewski, J., M.O. Nowicki, A. Bronisz, G. Nuovo, J. Palatini, M. De Lay, J. Van Brocklyn, M.C. Ostrowski, E.A. Chiocca, and S.E. Lawler. 2010. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Molecular Cell 37: 620–632.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Goodwin, J.M., R.U. Svensson, H.J. Lou, M.M. Winslow, B.E. Turk, and R.J. Shaw. 2014. An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential. Molecular Cell 55: 436–450.

    Article  CAS  PubMed  Google Scholar 

  • Gowans, G.J., S.A. Hawley, F.A. Ross, and D.G. Hardie. 2013. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metabolism 18: 556–566.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hadad, S.M., S. Fleming, and A.M. Thompson. 2008. Targeting AMPK: a new therapeutic opportunity in breast cancer. Critical reviews in oncology/hematology 67: 1–7.

    Article  PubMed  Google Scholar 

  • Hardie, D.G., and D.R. Alessi. 2013. LKB1 and AMPK and the cancer-metabolism link - ten years after. BMC Biology 11: 36.

    Article  PubMed Central  PubMed  Google Scholar 

  • Hardie, D.G., F.A. Ross, and S.A. Hawley. 2012. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Reviews Molecular Cell Biology 13: 251–262.

    Article  CAS  PubMed  Google Scholar 

  • Hawley, S.A., J. Boudeau, J.L. Reid, K.J. Mustard, L. Udd, T.P. Makela, D.R. Alessi, and D.G. Hardie. 2003. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. Journal of biology 2: 28.

    Article  PubMed Central  PubMed  Google Scholar 

  • Hawley, S.A., D.A. Pan, K.J. Mustard, L. Ross, J. Bain, A.M. Edelman, B.G. Frenguelli, and D.G. Hardie. 2005. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metabolism 2: 9–19.

    Article  CAS  PubMed  Google Scholar 

  • Hawley, S.A., F.A. Ross, C. Chevtzoff, K.A. Green, A. Evans, S. Fogarty, M.C. Towler, L.J. Brown, O.A. Ogunbayo, A.M. Evans, and D.G. Hardie. 2010. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metabolism 11: 554–565.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hemminki, A., D. Markie, I. Tomlinson, E. Avizienyte, S. Roth, A. Loukola, G. Bignell, W. Warren, M. Aminoff, P. Hoglund, H. Jarvinen, P. Kristo, K. Pelin, M. Ridanpaa, R. Salovaara, T. Toro, W. Bodmer, S. Olschwang, A.S. Olsen, M.R. Stratton, A. De La Chapelle, and L.A. Aaltonen. 1998. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391: 184–187.

    Article  CAS  PubMed  Google Scholar 

  • Hindupur, S.K., S.A. Balaji, M. Saxena, S. Pandey, G. Sravan, N. Heda, M. Kumar, G. Mukherjee, D. Dey, and A. Rangarajan. 2014. Identification of a novel AMPK-PEA15 axis in the anoikis-resistant growth of mammary cells. Breast cancer research : BCR 16: 420.

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Honjo, S., J.A. Ajani, A.W. Scott, Q. Chen, H.D. Skinner, J. Stroehlein, R.L. Johnson, and S. Song. 2014. Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. International Journal of Oncology 45: 567–574.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Inoki, K., T. Zhu, and K.L. Guan. 2003. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115: 577–590.

    Article  CAS  PubMed  Google Scholar 

  • Jang, T., J.M. Calaoagan, E. Kwon, S. Samuelsson, L. Recht, and K.R. Laderoute. 2011. 5′-AMP-activated protein kinase activity is elevated early during primary brain tumor development in the rat. International journal of cancer. Journal international du cancer 128: 2230–2239.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Janzer, A., N.J. German, K.N. Gonzalez-Herrera, J.M. Asara, M.C. Haigis, and K. Struhl. 2014. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proceedings of the National Academy of Sciences of the United States of America 111: 10574–10579.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jeon, S.M., and N. Hay. 2012. The dark face of AMPK as an essential tumor promoter. Cellular logistics 2: 197–202.

    Article  PubMed Central  PubMed  Google Scholar 

  • Ji, H., M.R. Ramsey, D.N. Hayes, C. Fan, K. Mcnamara, P. Kozlowski, C. Torrice, M.C. Wu, T. Shimamura, S.A. Perera, M.C. Liang, D. Cai, G.N. Naumov, L. Bao, C.M. Contreras, D. Li, L. Chen, J. Krishnamurthy, J. Koivunen, L.R. Chirieac, R.F. Padera, R.T. Bronson, N.I. Lindeman, D.C. Christiani, X. Lin, G.I. Shapiro, P.A. Janne, B.E. Johnson, M. Meyerson, D.J. Kwiatkowski, D.H. Castrillon, N. Bardeesy, N.E. Sharpless, and K.K. Wong. 2007. LKB1 modulates lung cancer differentiation and metastasis. Nature 448: 807–810.

    Article  CAS  PubMed  Google Scholar 

  • Kato, K., T. Ogura, A. Kishimoto, Y. Minegishi, N. Nakajima, M. Miyazaki, and H. Esumi. 2002. Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. Oncogene 21: 6082–6090.

    Article  CAS  PubMed  Google Scholar 

  • Kim, I., and Y.Y. He. 2013. Targeting the AMP-activated protein kinase for cancer prevention and therapy. Frontiers in oncology 3: 175.

    PubMed Central  PubMed  Google Scholar 

  • Laderoute, K.R., K. Amin, J.M. Calaoagan, M. Knapp, T. Le, J. Orduna, M. Foretz, and B. Viollet. 2006. 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Molecular and Cellular Biology 26: 5336–5347.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Laderoute, K.R., J.M. Calaoagan, W.R. Chao, D. Dinh, N. Denko, S. Duellman, J. Kalra, X. Liu, I. Papandreou, L. Sambucetti, and L.G. Boros. 2014. 5′-AMP-activated protein kinase (AMPK) supports the growth of aggressive experimental human breast cancer tumors. The Journal of biological chemistry 289: 22850–22864.

    Article  CAS  PubMed  Google Scholar 

  • Laderoute, K.R., J.M. Calaoagan, P.B. Madrid, A.E. Klon, and P.J. Ehrlich. 2010. SU11248 (sunitinib) directly inhibits the activity of mammalian 5′-AMP-activated protein kinase (AMPK). Cancer Biology & Therapy 10: 68–76.

    Article  CAS  Google Scholar 

  • Liang, J., and G.B. Mills. 2013. AMPK: a contextual oncogene or tumor suppressor? Cancer Research 73: 2929–2935.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu, L., J. Ulbrich, J. Muller, T. Wustefeld, L. Aeberhard, T.R. Kress, N. Muthalagu, L. Rycak, R. Rudalska, R. Moll, S. Kempa, L. Zender, M. Eilers, and D.J. Murphy. 2012. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 483: 608–612.

    Article  CAS  PubMed  Google Scholar 

  • Liu, X., R.R. Chhipa, S. Pooya, M. Wortman, S. Yachyshin, L.M. Chow, A. Kumar, X. Zhou, Y. Sun, B. Quinn, C. Mcpherson, R.E. Warnick, A. Kendler, S. Giri, J. Poels, K. Norga, B. Viollet, G.A. Grabowski, and B. Dasgupta. 2014. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proceedings of the National Academy of Sciences of the United States of America 111: E435–E444.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lonardo, E., M. Cioffi, P. Sancho, Y. Sanchez-Ripoll, S.M. Trabulo, J. Dorado, A. Balic, M. Hidalgo, and C. Heeschen. 2013. Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS ONE 8: e76518.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Massie, C.E., A. Lynch, A. Ramos-Montoya, J. Boren, R. Stark, L. Fazli, A. Warren, H. Scott, B. Madhu, N. Sharma, H. Bon, V. Zecchini, D.M. Smith, G.M. Denicola, N. Mathews, M. Osborne, J. Hadfield, S. Macarthur, B. Adryan, S.K. Lyons, K.M. Brindle, J. Griffiths, M.E. Gleave, P.S. Rennie, D.E. Neal, and I.G. Mills. 2011. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. The EMBO journal 30: 2719–2733.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mizrachy-Schwartz, S., N. Cohen, S. Klein, N. Kravchenko-Balasha, and A. Levitzki. 2011. Up-regulation of AMP-activated protein kinase in cancer cell lines is mediated through c-Src activation. The Journal of biological chemistry 286: 15268–15277.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mohseni, M., J. Sun, A. Lau, S. Curtis, J. Goldsmith, V.L. Fox, C. Wei, M. Frazier, O. Samson, K.K. Wong, C. Kim, and F.D. Camargo. 2014. A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nature Cell Biology 16: 108–117.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mungai, P.T., G.B. Waypa, A. Jairaman, M. Prakriya, D. Dokic, M.K. Ball, and P.T. Schumacker. 2011. Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Molecular and Cellular Biology 31: 3531–3545.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nair, V., S. Sreevalsan, R. Basha, M. Abdelrahim, A. Abudayyeh, Hoffman.A. Rodrigues, and S. Safe. 2014. Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors. The Journal of biological chemistry 289: 27692–27701.

    Article  CAS  PubMed  Google Scholar 

  • Ng, T.L., G. Leprivier, M.D. Robertson, C. Chow, M.J. Martin, K.R. Laderoute, E. Davicioni, T.J. Triche, and P.H. Sorensen. 2012. The AMPK stress response pathway mediates anoikis resistance through inhibition of mTOR and suppression of protein synthesis. Cell Death and Differentiation 19: 501–510.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Phoenix, K.N., C.V. Devarakonda, M.M. Fox, L.E. Stevens, and K.P. Claffey. 2012. AMPKalpha2 suppresses murine embryonic fibroblast transformation and tumorigenesis. Genes and cancer 3: 51–62.

    Article  PubMed Central  PubMed  Google Scholar 

  • Pollak, M. 2013. Potential applications for biguanides in oncology. The Journal of Clinical Investigation 123: 3693–3700.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Possik, E., Z. Jalali, Y. Nouet, M. Yan, M.C. Gingras, K. Schmeisser, L. Panaite, F. Dupuy, D. Kharitidi, L. Chotard, R.G. Jones, D.H. Hall, and A. Pause. 2014. Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS Genetics 10: e1004273.

    Article  PubMed Central  PubMed  Google Scholar 

  • Rios, M., M. Foretz, B. Viollet, A. Prieto, M. Fraga, J.A. Costoya, and R. Senaris. 2013. AMPK activation by oncogenesis is required to maintain cancer cell proliferation in astrocytic tumors. Cancer Research 73: 2628–2638.

    Article  CAS  PubMed  Google Scholar 

  • Ros, S., C.R. Santos, S. Moco, F. Baenke, G. Kelly, M. Howell, N. Zamboni, and A. Schulze. 2012. Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival. Cancer discovery 2: 328–343.

    Article  CAS  PubMed  Google Scholar 

  • Rosilio, C., N. Lounnas, M. Nebout, V. Imbert, T. Hagenbeek, H. Spits, V. Asnafi, R. Pontier-Bres, J. Reverso, J.F. Michiels, I.B. Sahra, F. Bost, and J.F. Peyron. 2013. The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells. Cancer Letters 336: 114–126.

    Article  CAS  PubMed  Google Scholar 

  • Sahra, I.B., C. Regazzetti, G. Robert, K. Laurent, Y. Le Marchand-Brustel, P. Auberger, J.F. Tanti, S. Giorgetti-Peraldi, and F. Bost. 2011. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Research 71(13): 4366–4372.

    Article  PubMed  Google Scholar 

  • Schafer, Z.T., A.R. Grassian, L. Song, Z. Jiang, Z. Gerhart-Hines, H.Y. Irie, S. Gao, P. Puigserver, and J.S. Brugge. 2009. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461: 109–113.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shank, J.J., K. Yang, J. Ghannam, L. Cabrera, C.J. Johnston, R.K. Reynolds, and R.J. Buckanovich. 2012. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecologic Oncology 127: 390–397.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • She, C., L.Q. Zhu, Y.F. Zhen, X.D. Wang, and Q.R. Dong. 2014. Activation of AMPK protects against hydrogen peroxide-induced osteoblast apoptosis through autophagy induction and NADPH maintenance: new implications for osteonecrosis treatment? Cellular Signalling 26: 1–8.

    Article  CAS  PubMed  Google Scholar 

  • Sinnett, S.E., and J.E. Brenman. 2014. Past strategies and future directions for identifying AMP-activated protein kinase (AMPK) modulators. Pharmacology & Therapeutics 143: 111–118.

    Article  CAS  Google Scholar 

  • Song, C.W., H. Lee, R.P. Dings, B. Williams, J. Powers, T.D. Santos, B.H. Choi, and H.J. Park. 2012. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Scientific reports 2: 362.

    PubMed Central  PubMed  Google Scholar 

  • Steinberg, G.R., and B.E. Kemp. 2009. AMPK in health and disease. Physiological Reviews 89: 1025–1078.

    Article  CAS  PubMed  Google Scholar 

  • Tennakoon, J.B., Y. Shi, J.J. Han, E. Tsouko, M.A. White, A.R. Burns, A. Zhang, X. Xia, O.R. Ilkayeva, L. Xin, M.M. Ittmann, F.G. Rick, A.V. Schally, and D.E. Frigo. 2013. Androgens regulate prostate cancer cell growth via an AMPK-PGC-1alpha-mediated metabolic switch. Oncogene. 33(45): 5251–5261.

    Article  PubMed  Google Scholar 

  • Vazquez-Martin, A., C. Oliveras-Ferraros, S. Del Barco, B. Martin-Castillo, and J.A. Menendez. 2011. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Research and Treatment 126: 355–364.

    Article  CAS  PubMed  Google Scholar 

  • Viale, A., P. Pettazzoni, C.A. Lyssiotis, H. Ying, N. Sanchez, M. Marchesini, A. Carugo, T. Green, S. Seth, V. Giuliani, M. Kost-Alimova, F. Muller, S. Colla, L. Nezi, G. Genovese, A.K. Deem, A. Kapoor, W. Yao, E. Brunetto, Y. Kang, M. Yuan, J.M. Asara, Y.A. Wang, T.P. Heffernan, A.C. Kimmelman, H. Wang, J.B. Fleming, L.C. Cantley, R.A. Depinho, and G.F. Draetta. 2014. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514(7524): 628–632.

    Article  CAS  PubMed  Google Scholar 

  • Vincent, E. E., P.P. Coelho, J. Blagih, T. Griss, B. Viollet, and R.G. Jones, 2014. Differential effects of AMPK agonists on cell growth and metabolism. Oncogene. doi:10.1038/onc.2014.301.

  • Woods, A., K. Dickerson, R. Heath, S.P. Hong, M. Momcilovic, S.R. Johnstone, M. Carlson, and D. Carling. 2005. Ca2 +/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metabolism 2: 21–33.

    Article  CAS  PubMed  Google Scholar 

  • Woods, A., S.R. Johnstone, K. Dickerson, F.C. Leiper, L.G. Fryer, D. Neumann, U. Schlattner, T. Wallimann, M. Carlson, and D. Carling. 2003. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Current biology: CB 13: 2004–2008.

    Article  CAS  PubMed  Google Scholar 

  • Xu, C., C.M. Fillmore, S. Koyama, H. Wu, Y. Zhao, Z. Chen, G.S. Herter-Sprie, E.A. Akbay, J.H. Tchaicha, A. Altabef, J.B. Reibel, Z. Walton, H. Ji, H. Watanabe, P.A. Janne, D.H. Castrillon, A.K. Rustgi, A.J. Bass, G.J. Freeman, R.F. Padera, G. Dranoff, P.S. Hammerman, C.F. Kim, and K.K. Wong. 2014. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 25: 590–604.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yan, M., M.C. Gingras, E.A. Dunlop, Y. Nouet, F. Dupuy, Z. Jalali, E. Possik, B.J. Coull, D. Kharitidi, A.B. Dydensborg, B. Faubert, M. Kamps, S. Sabourin, R.S. Preston, D.M. Davies, T. Roughead, L. Chotard, M.A. Van Steensel, R. Jones, A.R. Tee, and A. Pause. 2014. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. The Journal of Clinical Investigation 124: 2640–2650.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang, Y.L., H. Guo, C.S. Zhang, S.Y. Lin, Z. Yin, Y. Peng, H. Luo, Y. Shi, G. Lian, C. Zhang, M. Li, Z. Ye, J. Ye, J. Han, P. Li, J.W. Wu, and S.C. Lin. 2013. AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation. Cell Metabolism 18: 546–555.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, G., R. Myers, Y. Li, Y. Chen, X. Shen, J. Fenyk-Melody, M. Wu, J. Ventre, T. Doebber, N. Fujii, N. Musi, M.F. Hirshman, L.J. Goodyear, and D.E. Moller. 2001. Role of AMP-activated protein kinase in mechanism of metformin action. The Journal of Clinical Investigation 108: 1167–1174.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zmijewski, J.W., S. Banerjee, H. Bae, A. Friggeri, E.R. Lazarowski, and E. Abraham. 2010. Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. The Journal of biological chemistry 285: 33154–33164.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledegments

This work was supported by grants from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (S2014-A0251-00001) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (S2014-A0403-00067).

Author information

Authors and Affiliations

  1. College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, 443-749, Republic of Korea

    Sang-Min Jeon

  2. Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60607, USA

    Nissim Hay

Authors
  1. Sang-Min Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nissim Hay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sang-Min Jeon.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jeon, SM., Hay, N. The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch. Pharm. Res. 38, 346–357 (2015). https://doi.org/10.1007/s12272-015-0549-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-015-0549-z

Keywords

Search

Navigation