Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α

Proceedings of the National Academy of Sciences of the United States of America

Volumn 111, Issue 7, 2014, Pages 2554-2559

  Faubert, Brandon ^a,b   Vincent, Emma E ^a,b   Griss, Takla ^a,b   Samborska, Bozena ^a,b   Izreig, Said ^a,b   Svensson, Robert U ^c   Mamer, Orval A ^a,b   Avizonis, Daina ^a,b   Shackelford, David B ^d   Shaw, Reuben J ^c   Jones, Russell G ^a,b  

^a MCGILL UNIVERSITY   (Canada)

^b MCGILL UNIVERSITY   (Canada)

^c HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Cancer metabolism; Glutamine metabolism; HIF 1alpha; Peutz Jeghers Syndrome; PJS; Warburg effect

Indexed keywords

ADENOSINE TRIPHOSPHATE; FRUCTOSE BISPHOSPHATE ALDOLASE; GLUCOSE; GLUTAMINE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; LACTATE DEHYDROGENASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; PROTEIN KINASE LKB1; PYRUVATE DEHYDROGENASE KINASE; REACTIVE OXYGEN METABOLITE;

AMINO ACID METABOLISM; ANIMAL CELL; APOPTOSIS; ARTICLE; BIOSYNTHESIS; CANCER CELL; CANCER GROWTH; CELL GROWTH; CELL METABOLISM; CELL PROLIFERATION; CELL SURVIVAL; CITRIC ACID CYCLE; CONTROLLED STUDY; GLUCOSE METABOLISM; GLYCOLYSIS; GROWTH REGULATION; IMMUNOBLOTTING; MACROMOLECULE; METABOLIC REGULATION; MOUSE; NONHUMAN; NUCLEAR REPROGRAMMING; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION;

CANCER METABOLISM; GLUTAMINE METABOLISM; HIF-1ALPHA; PEUTZ-JEGHERS SYNDROME; PJS; WARBURG EFFECT;

ADENOSINE TRIPHOSPHATE; ANALYSIS OF VARIANCE; ANIMALS; APOPTOSIS; BLOTTING, WESTERN; CELL LINE, TUMOR; CELL PROLIFERATION; ENERGY METABOLISM; FIBROBLASTS; GAS CHROMATOGRAPHY-MASS SPECTROMETRY; GLUCOSE; GLUTAMINE; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; METABOLIC NETWORKS AND PATHWAYS; MICE; MULTIPROTEIN COMPLEXES; OXYGEN CONSUMPTION; PROTEIN-SERINE-THREONINE KINASES; REACTIVE OXYGEN SPECIES; TOR SERINE-THREONINE KINASES;

EID: 84894359469     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1312570111     Document Type: Article

References (42)

1. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11-20.
2. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324(5930):1029-1033.
3. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB (2008) Brick by brick: Metabolism and tumor cell growth. Curr Opin Genet Dev 18(1):54-61.
4. Jones RG, Thompson CB (2009) Tumor suppressors and cell metabolism: A recipe for cancer growth. Genes Dev 23(5):537-548.
5. Pan JG, Mak TW (2007) Metabolic targeting as an anticancer strategy: Dawn of a new era? Sci STKE 2007(381):pe14.
6. Semenza GL (2011) Oxygen sensing, homeostasis, and disease. N Engl JMed 365(6):537-547.
7. Keith B, Johnson RS, Simon MC (2012) HIF1a and HIF2a: Sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12(1):9-22.
8. Giatromanolaki A, et al. (2001) Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer 85(6):881-890.
9. Roy BC, et al. (2010) Involvement of LKB1 in epithelial-mesenchymal transition (EMT) of human lung cancer cells. Lung Cancer 70(2):136-145.
10. Hemminki A, et al. (1998) A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391(6663):184-187.
11. Avizienyte E, et al. (1999) LKB1 somatic mutations in sporadic tumors. Am J Pathol 154(3):677-681.
12. Contreras CM, et al. (2008) Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas. Cancer Res 68(3):759-766.
13. Wingo SN, et al. (2009) Somatic LKB1 mutations promote cervical cancer progression. PLoS ONE 4(4):e5137.
14. Sanchez-Cespedes M, et al. (2002) Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 62(13):3659-3662.
15. Hearle N, et al. (2006) Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12(10):3209-3215.
16. Shackelford DB, Shaw RJ (2009) The LKB1-AMPK pathway: Metabolism and growth control in tumour suppression. Nat Rev Cancer 9(8):563-575.
17. Shaw RJ (2008) LKB1: Cancer, polarity, metabolism, and now fertility. Biochem J 416(1): E1-e3.
18. Boudeau J, Sapkota G, Alessi DR (2003) LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Lett 546(1):159-165.
19. Shackelford DB, et al. (2009) mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc Natl Acad Sci USA 106(27):11137-11142.
20. Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL (2004) Regulation of the TSC pathway by LKB1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18(13):1533-1538.
21. Shaw RJ, et al. (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6(1):91-99.
22. Xu Q, Vu H, Liu L, Wang TC, Schaefer WH (2011) Metabolic profiles show specific mitochondrial toxicities in vitro in myotube cells. J Biomol NMR 49(3-4):207-219.
23. Shackelford DB, et al. (2013) LKB1 inactivation dictates therapeutic response of nonsmall cell lung cancer to the metabolism drug phenformin. Cancer Cell 23(2):143-158.
24. Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG, Jr. (2003) TSC2 regulates VEGF through mTOR-dependent and-independent pathways. Cancer Cell 4(2):147-158.
25. Guzy RD, et al. (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1(6):401-408.
26. Mansfield KD, et al. (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 1(6):393-399.
27. Brunelle JK, et al. (2005) Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab 1(6):409-414.
28. Horak P, et al. (2010) Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis. Proc Natl Acad Sci USA 107(10):4675-4680.
29. Semenza GL (2011) Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb Symp Quant Biol 76:347-353.
30. Nicholls DG (2009) Spare respiratory capacity, oxidative stress and excitotoxicity. Biochem Soc Trans 37(Pt 6):1385-1388.
31. Hatzivassiliou G, et al. (2005) ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8(4):311-321.
32. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177-185.
33. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3(3): 187-197.
34. Metallo CM, et al. (2012) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481(7381):380-384.
35. Mullen AR, et al. (2012) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481(7381):385-388.
36. Wise DR, et al. (2011) Hypoxia promotes isocitrate dehydrogenase- dependent carboxylation of a-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci USA 108(49):19611-19616.
37. Faubert B, et al. (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17(1):113-124.
38. Hardie DG, Alessi DR (2013) LKB1 and AMPK and the cancer-metabolism link: Ten years after. BMC Biol 11:36.
39. Ying H, et al. (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149(3):656-670.
40. Makowski L, Hayes DN (2008) Role of LKB1 in lung cancer development. Br J Cancer 99(5):683-688.
41. Ji H, et al. (2007) LKB1 modulates lung cancer differentiation and metastasis. Nature 448(7155):807-810.
42. Jones RG, et al. (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18(3):283-293.