LKB1 Inactivation Dictates Therapeutic Response of Non-Small Cell Lung Cancer to the Metabolism Drug Phenformin

Cancer Cell

Volumn 23, Issue 2, 2013, Pages 143-158

  Shackelford, David B ^a,c   Abt, Evan ^c   Gerken, Laurie ^a   Vasquez, Debbie S ^a   Seki, Atsuko ^c   Leblanc, Mathias ^a   Wei, Liu ^c   Fishbein, Michael C ^c   Czernin, Johannes ^c   Mischel, Paul S ^c,d   Shaw, Reuben J ^a,b  

^a SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

^b HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d LUDWIG INSTITUTE FOR CANCER RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CASPASE 3; INITIATION FACTOR 2ALPHA; K RAS PROTEIN; METFORMIN; PHENFORMIN; PROTEIN KINASE LKB1; PROTEIN P53;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER GROWTH; CANCER SIZE; CANCER SURVIVAL; CONTROLLED STUDY; DRUG METABOLISM; ENZYME INACTIVATION; FLOW CYTOMETRY; HUMAN; HUMAN CELL; LUNG NON SMALL CELL CANCER; METABOLIC STRESS; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; MITOPHAGY; MOLECULARLY TARGETED THERAPY; MOUSE; NONHUMAN; OXYGEN CONSUMPTION; POST TREATMENT SURVIVAL; PRIORITY JOURNAL; PROTEIN EXPRESSION; TREATMENT RESPONSE;

EID: 84873584845     PISSN: 15356108     EISSN: 18783686     Source Type: Journal    
DOI: 10.1016/j.ccr.2012.12.008     Document Type: Article

References (52)

1. Algire C., Amrein L., Bazile M., David S., Zakikhani M., Pollak M. Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene 2011, 30:1174-1182.
2. Anisimov V.N., Berstein L.M., Egormin P.A., Piskunova T.S., Popovich I.G., Zabezhinski M.A., Kovalenko I.G., Poroshina T.E., Semenchenko A.V., Provinciali M., et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp. Gerontol 2005, 40:685-693.
3. Appleyard M.V., Murray K.E., Coates P.J., Wullschleger S., Bray S.E., Kernohan N.M., Fleming S., Alessi D.R., Thompson A.M. Phenformin as prophylaxis and therapy in breast cancer xenografts. Br. J. Cancer 2012, 106:1117-1122.
4. Birsoy K., Sabatini D.M., Possemato R. Untuning the tumor metabolic machine: Targeting cancer metabolism: a bedside lesson. Nat. Med. 2012, 18:1022-1023.
5. Buzzai M., Jones R.G., Amaravadi R.K., Lum J.J., DeBerardinis R.J., Zhao F., Viollet B., Thompson C.B. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007, 67:6745-6752.
6. Carretero J., Shimamura T., Rikova K., Jackson A.L., Wilkerson M.D., Borgman C.L., Buttarazzi M.S., Sanofsky B.A., McNamara K.L., Brandstetter K.A., et al. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell 2010, 17:547-559.
7. Chae Y.C., Caino M.C., Lisanti S., Ghosh J.C., Dohi T., Danial N.N., Villanueva J., Ferrero S., Vaira V., Santambrogio L., et al. Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s. Cancer Cell 2012, 22:331-344.
8. Chen Z., Cheng K., Walton Z., Wang Y., Ebi H., Shimamura T., Liu Y., Tupper T., Ouyang J., Li J., et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 2012, 483:613-617.
9. Crofford O.B. Metformin. N. Engl. J. Med. 1995, 333:588-589.
10. Ding L., Getz G., Wheeler D.A., Mardis E.R., McLellan M.D., Cibulskis K., Sougnez C., Greulich H., Muzny D.M., Morgan M.B., et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008, 455:1069-1075.
11. Dowling R.J., Niraula S., Stambolic V., Goodwin P.J. Metformin in cancer: translational challenges. J. Mol. Endocrinol. 2012, 48:R31-R43.
12. Dykens J.A., Jamieson J., Marroquin L., Nadanaciva S., Billis P.A., Will Y. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol. Appl. Pharmacol. 2008, 233:203-210.
13. Egan D.F., Shackelford D.B., Mihaylova M.M., Gelino S., Kohnz R.A., Mair W., Vasquez D.S., Joshi A., Gwinn D.M., Taylor R., et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 2011, 331:456-461.
14. El-Mir M.Y., Nogueira V., Fontaine E., Avéret N., Rigoulet M., Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 2000, 275:223-228.
15. 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 2005, 330:1304-1305.
16. Farago A.F., Snyder E.L., Jacks T. SnapShot: Lung cancer models. Cell 2012, 149:246. 246 e241.
17. Foretz M., Hebrard S., Leclerc J., Zarrinpashneh E., Soty M., Mithieux G., Sakamoto K., Andreelli F., Viollet B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest 2010, 120:2355-2369.
18. 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. Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. Oncogene 2011, 30:3784-3791.
19. Gwinn D.M., Shackelford D.B., Egan D.F., Mihaylova M.M., Mery A., Vasquez D.S., Turk B.E., Shaw R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 2008, 30:214-226.
20. Hardie D.G., Ross F.A., Hawley S.A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 2012, 13:251-262.
21. Hawley S.A., Ross F.A., Chevtzoff C., Green K.A., Evans A., Fogarty S., Towler M.C., Brown L.J., Ogunbayo O.A., Evans A.M., Hardie D.G. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 2010, 11:554-565.
22. Hemminki A., Markie D., Tomlinson I., Avizienyte E., Roth S., Loukola A., Bignell G., Warren W., Aminoff M., Höglund P., et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998, 391:184-187.
23. Hirst J., King M.S., Pryde K.R. The production of reactive oxygen species by complex I. Biochem. Soc. Trans. 2008, 36:976-980.
24. Huang X., Wullschleger S., Shpiro N., McGuire V.A., Sakamoto K., Woods Y.L., McBurnie W., Fleming S., Alessi D.R. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem. J. 2008, 412:211-221.
25. Inoki K., Zhu T., Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115:577-590.
26. Jackson E.L., Olive K.P., Tuveson D.A., Bronson R., Crowley D., Brown M., Jacks T. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 2005, 65:10280-10288.
27. Jeon S.M., Chandel N.S., Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 2012, 485:661-665.
28. Ji H., Ramsey M.R., Hayes D.N., Fan C., McNamara K., Kozlowski P., Torrice C., Wu M.C., Shimamura T., Perera S.A., et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 2007, 448:807-810.
29. Jin S., DiPaola R.S., Mathew R., White E. Metabolic catastrophe as a means to cancer cell death. J. Cell Sci. 2007, 120:379-383.
30. Jonkers J., Meuwissen R., van der Gulden H., Peterse H., van der Valk M., Berns A. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 2001, 29:418-425.
31. Kalender A., Selvaraj A., Kim S.Y., Gulati P., Brule S., Viollet B., Kemp B.E., Bardeesy N., Dennis P., Schlager J.J., et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010, 11:390-401.
32. Kushnareva Y., Murphy A.N., Andreyev A. Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation reduction state. Biochem. J. 2002, 368:545-553.
33. Laderoute K.R., Amin K., Calaoagan J.M., Knapp M., Le T., Orduna J., Foretz M., Viollet B. 5'-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol. Cell. Biol. 2006, 26:5336-5347.
34. Liang M.C., Ma J., Chen L., Kozlowski P., Qin W., Li D., Goto J., Shimamura T., Hayes D.N., Meyerson M., et al. TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity. Oncogene 2010, 29:1588-1597.
35. Memmott R.M., Mercado J.R., Maier C.R., Kawabata S., Fox S.D., Dennis P.A. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev. Res. (Phila.) 2010, 3:1066-1076.
36. Motta D.A. Metformin in the treatment of polycystic ovary syndrome. Curr. Pharm. Des. 2008, 14:2121-2125.
37. Muaddi H., Majumder M., Peidis P., Papadakis A.I., Holcik M., Scheuner D., Kaufman R.J., Hatzoglou M., Koromilas A.E. Phosphorylation of eIF2α at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency. Mol. Biol. Cell 2010, 21:3220-3231.
38. Nakada D., Saunders T.L., Morrison S.J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 2010, 468:653-658.
39. Osoegawa A., Kometani T., Nosaki K., Ondo K., Hamatake M., Hirai F., Seto T., Sugio K., Ichinose Y. LKB1 mutations frequently detected in mucinous bronchioloalveolar carcinoma. Jpn. J. Clin. Oncol. 2011, 41:1132-1137.
40. 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. 2000, 348:607-614.
41. Pollak M. Metformin and other biguanides in oncology: advancing the research agenda. Cancer Prev. Res. (Phila.) 2010, 3:1060-1065.
42. Pollak M.N. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2012, 2:778-790.
43. Safran M., Kim W.Y., Kung A.L., Horner J.W., DePinho R.A., Kaelin W.G. Mouse reporter strain for noninvasive bioluminescent imaging of cells that have undergone Cre-mediated recombination. Mol. Imaging 2003, 2:297-302.
44. Sakamoto K., McCarthy A., Smith D., Green K.A., Grahame Hardie D., Ashworth A., Alessi D.R. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 2005, 24:1810-1820.
45. Sanchez-Cespedes M., Parrella P., Esteller M., Nomoto S., Trink B., Engles J.M., Westra W.H., Herman J.G., Sidransky D. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 2002, 62:3659-3662.
46. Shackelford D.B., Shaw R.J. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 2009, 9:563-575.
47. Shackelford D.B., Vasquez D.S., Corbeil J., Wu S., Leblanc M., Wu C.L., Vera D.R., Shaw R.J. mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc. Natl. Acad. Sci. USA 2009, 106:11137-11142.
48. Shaw R.J., Kosmatka M., Bardeesy N., Hurley R.L., Witters L.A., DePinho R.A., Cantley L.C. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. USA 2004, 101:3329-3335.
49. Shaw R.J., Lamia K.A., Vasquez D., Koo S.H., Bardeesy N., Depinho R.A., Montminy M., Cantley L.C. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005, 310:1642-1646.
50. 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. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J. Clin. Invest. 2007, 117:1422-1431.
51. Taubes G. Cancer research. Cancer prevention with a diabetes pill?. Science 2012, 335:29.
52. Ye J., Kumanova M., Hart L.S., Sloane K., Zhang H., De Panis D.N., Bobrovnikova-Marjon E., Diehl J.A., Ron D., Koumenis C. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 2010, 29:2082-2096.