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Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

Oncogene volume 30, pages 1174–1182 (2011)Cite this article

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Abstract

Hypothesis-generating epidemiological research has suggested that cancer burden is reduced in diabetics treated with metformin and experimental work has raised questions regarding the role of direct adenosine monophosphate-activated protein kinase (AMPK)-mediated anti-neoplastic effects of metformin as compared with indirect effects attributable to reductions in circulating insulin levels in the host. We treated both tumor LKB1 expression and host diet as variables, and observed that metformin inhibited tumor growth and reduced insulin receptor activation in tumors of mice with diet-induced hyperinsulinemia, independent of tumor LKB1 expression. In the absence of hyperinsulinemia, metformin inhibited only the growth of tumors transfected with short hairpin RNA against LKB1, a finding attributable neither to an effect on host insulin level nor to activation of AMPK within the tumor. Further investigation in vitro showed that cells with reduced LKB1 expression are more sensitive to metformin-induced adenosine triphosphate depletion owing to impaired ability to activate LKB1-AMPK-dependent energy-conservation mechanisms. Thus, loss of function of LKB1 can accelerate proliferation in contexts where it functions as a tumor suppressor, but can also sensitize cells to metformin. These findings predict that any clinical utility of metformin or similar compounds in oncology will be restricted to subpopulations defined by host insulin levels and/or loss of function of LKB1.

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References

  • Algire C, Amrein L, Zakikhani M, Panasci L, 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 acid synthase. Endocr Relat Cancer 17: 351–360.

    Article  CAS  Google Scholar 

  • Algire C, Zakikhani M, Blouin M-J, Shuai JH, Pollak M . (2008). Metformin attenuates the stimulatory effect of a high energy diet on in vivo H59 carcinoma growth. Endocr Relat Cancer 15: 833–839.

    Article  CAS  Google Scholar 

  • Blake DA, McLean NV . (1989). A colorimetric assay for the measurement of -glucose consumption by cultured cells. Anal Biochem 177: 156–160.

    Article  CAS  Google Scholar 

  • Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR, Meier CR . (2010). Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 33: 1304–1308.

    Article  CAS  Google Scholar 

  • Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F et al. (2007). Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67: 6745–6752.

    Article  CAS  Google Scholar 

  • Currie CJ, Poole CD, Gale EA . (2009). The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52: 1766–1777.

    Article  CAS  Google Scholar 

  • DeFronzo RA, Goodman AM . (1995). Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 333: 541–549.

    Article  CAS  Google Scholar 

  • Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N . (2007). Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67: 10804–10812.

    Article  CAS  Google Scholar 

  • Dykens JA, Jamieson J, Marroquin L, Nadanaciva S, Billis PA, Will Y . (2008). 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.

    Article  CAS  Google Scholar 

  • Engelman, Cantley . (2010). Chemoprevention meets glucose control. Can Prev Res 3: 1049–1052.

    Article  CAS  Google Scholar 

  • El Mir MY, 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.

    Article  CAS  Google Scholar 

  • Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD . (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ 330: 1304–1305.

    Article  Google Scholar 

  • Fantin VR, St Pierre J, Leder P . (2006). Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9: 425–434.

    Article  CAS  Google Scholar 

  • Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G et al. (2010). Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 120: 2267–2270.

    Article  Google Scholar 

  • Hardie DG . (2006). Neither LKB1 nor AMPK are the direct targets of metformin. Gastroenterology 131: 973.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Hosono K, Endo H, Takahashi H, Sugiyama M, Sakai E, Uchiyama T et al. (2007). Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Can Prev Res 3: 1077–1083.

    Article  Google Scholar 

  • Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL et al. (2008). Important role of the LKB1-AMPK pathway in suppressing tumourigenesis in PTEN deficient mice. Biochem J 412: 211–221.

    Article  CAS  Google Scholar 

  • Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P et al. (2007). LKB1 modulates lung cancer differentiation and metastasis. Nature 448: 807–810.

    Article  CAS  Google Scholar 

  • Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y et al. (2005). AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18: 283–293.

    Article  CAS  Google Scholar 

  • Kalaany NY, Sabatini DM . (2009). Tumours with PI3K activation are resistant to dietary restriction. Nature 458: 725–731.

    Article  CAS  Google Scholar 

  • Kalender A, Selvaraj A, Kim SY, Gulati P, Brule S, Viollet B et al. (2010). Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 11: 390–401.

    Article  CAS  Google Scholar 

  • Kroemer G, Pouyssegur J . (2008). Tumor cell metabolism: cancer's Achilles’ heel. Cancer Cell 13: 472–482.

    Article  CAS  Google Scholar 

  • Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ . (2010). Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 33: 322–326.

    Article  CAS  Google Scholar 

  • Larsson SC, Mantzoros CS, Wolk A . (2007). Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 121: 856–862.

    Article  CAS  Google Scholar 

  • Larsson SC, Orsini N, Wolk A . (2005). Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 97: 1679–1687.

    Article  Google Scholar 

  • Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM . (2009). New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32: 1620–1625.

    Article  CAS  Google Scholar 

  • Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE et al. (2009). Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 8: 2031–2040.

    Article  CAS  Google Scholar 

  • Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA . (2010). Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Can Prev Res 3: 1066–1076.

    Article  CAS  Google Scholar 

  • Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y et al. (2010). Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res 70: 741–751.

    Article  CAS  Google Scholar 

  • Owen MR, Doran E, Halestrap AP . (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348 (Part 3): 607–614.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Pollak M . (2009). Do cancer cells care if their host is hungry? Cell Metab 9: 401–403.

    Article  CAS  Google Scholar 

  • Pollak M . (2010). Metformin and other biguanides in oncology: advancing the research agenda. Can Prev Res 3: 1060–1065.

    Article  CAS  Google Scholar 

  • Russell III RR, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M et al. (2004). AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 114: 495–503.

    Article  CAS  Google Scholar 

  • Sakamoto K, McCarthy A, Smith D, Green KA, Grahame HD, Ashworth A et al. (2005). Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J 24: 1810–1820.

    Article  CAS  Google Scholar 

  • Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM et al. (2002). Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 62: 3659–3662.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, Depinho RA et al. (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.

    Article  CAS  Google Scholar 

  • Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA et al. (2005). The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642–1646.

    Article  CAS  Google Scholar 

  • Tennant DA, Duran RV, Gottlieb E . (2010). Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10: 267–277.

    Article  CAS  Google Scholar 

  • Tomimoto A, Endo H, Sugiyama M, Fujisawa T, Hosono K, Takahashi H et al. (2008). Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci 99: 2136–2141.

    Article  CAS  Google Scholar 

  • van Lier MG, Wagner A, Mathus-Vliegen EM, Kuipers EJ, Steyerberg EW, van Leerdam ME . (2010). High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 105: 1258–1264.

    Article  CAS  Google Scholar 

  • Venkateswaran V, Haddad AQ, Fleshner NE, Fan R, Sugar LM, Nam R et al. (2007). Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts. J Natl Cancer Inst 99: 1793–1800.

    Article  Google Scholar 

  • Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R . (2009). Diabetes and cancer. Endocr Relat Cancer 16: 1103–1123.

    Article  CAS  Google Scholar 

  • Wingo SN, Gallardo TD, Akbay EA, Liang MC, Contreras CM, Boren T et al. (2009). Somatic LKB1 mutations promote cervical cancer progression. PLoS One 4: e5137.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN . (2008). The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila, PA) 1: 369–375.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr André Veillette for his advice and technical expertise, Dr Pnina Brodt for the MC38 cells, Drs Lawrence Panasci and Ernesto Schiffrin for sharing laboratory resources, and Dr Nahum Sonenberg and Dr Russell Jones for reviewing the manuscript prior to submission. This work was supported by a grant from the Terry Fox Research Institute. Ms Algire is supported through the Montréal Centre for Experimental Therapeutics in Cancer student fellowship and the Canadian Institute of Health Research Canada Graduate Fellowship.

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  1. Departments of Experimental Medicine and Oncology, E423 Segal Cancer Centre of the Jewish General Hospital, McGill University, Montréal, Québec, Canada

    C Algire & M Pollak

  2. Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada

    L Amrein, M Bazile, S David & M Zakikhani

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  1. C Algire
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Correspondence to M Pollak.

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Algire, C., Amrein, L., Bazile, M. et al. Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene 30, 1174–1182 (2011). https://doi.org/10.1038/onc.2010.483

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