Metabolomics-Edited Transcriptomics Analysis (META)

  • Teresa Whei-Mei FanEmail author
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


The study of the metabolome or systems biochemical functions in response to external agents such as drugs or toxicants is made possible by recent advances in NMR and mass spectrometry. By coupling the analytical technologies with the stable isotope tracer approach, it is also practical to map changes in metabolic networks with atomic resolution such that metabolic perturbations can be discerned at the enzyme reaction level. This information readily lends its use in guiding transcriptomic analysis for metabolic regulations at the transcriptional level—an approach called “Metabolomics-Edited Transcriptomic Analysis” or META. Two example studies are given to illustrate the use of uniformly 13C-labeled glucose tracer, 13C-isotopomer-based metabolomic analysis, and META for reconstructing metabolic pathways and for discerning their regulatory pathways. The first example describes a hypothetical investigation on the role of a “master” metabolic switch (AMP-activated protein kinase or AMPK) in regulating nucleic acid, lipid, and protein-related metabolism. NMR and GC-MS are complementarily used to obtain quantitative changes in metabolite and 13C-isotopomer profiles in a model cancer cell in response to AMPK activation (induced by AICAR, an adenosine analogue) or AMPK inactivation via siRNA knockdown. Expected findings from META that are consistent with known AMPK-mediated regulations include downregulation or phosphorylation of key proteins involved in the synthesis of fatty acids, phospholipids, and proteins. Scenarios for uncovering metabolic regulations previously unknown or contradictory to known AMPK actions are also given. The second example illustrates a real-world investigation on defining the multitargeted action of selenite in human lung adenocarcinoma A549 cells. The META approach revealed AMPK-mediated downregulation of fatty acid and protein synthesis, in addition to negative regulation of glycolysis, pentose phosphate pathway, Krebs cycle, glutathione synthesis, and nucleotide synthesis, as well as positive regulation of Gln metabolism. The complexity of the selenite action including the induction of opposing regulatory events was resolvable with the integrated metabolomics and transcriptomics approach, which is also generally applicable to any living system including the human body.

Key words

META metabolomics isotopomer analysis AMPK AICAR selenite A549 lung adenocarcinoma 



Acetyl CoA carboxylase


ATP citrate lyase




5-Aminoimidazole-4-carboxamide ribonucleoside




AMP-activated protein kinase


Adenine nucleotides


Carbohydrate-response-element-binding protein


Choline transporter


Cytosine nucleotides




Diacylglycerol kinase


Dihydroxyacetone phosphate


Eukaryotic elongation factor 2


Eukaryotic initiation factor 4E binding protein


Fatty acid synthase


Fructose bisphosphatase




Glucose-6-phosphate dehydrogenase




Glutamyl-cysteinyl ligase


Glutamate dehydrogenase

Glnase IP

Glutaminase interacting protein


Glucose transporter 4


Glycerol phosphate acyl transferase




Glycerol-3-phosphate dehydrogenase


Glycogen synthase


Reduced glutathione


Oxidized glutathione


Guanine nucleotides


3-Hydroxy-3-methylglutaryl-coenzyme A reductase


Heteronuclear single quantum coherence spectroscopy


Inducible phosphofructokinase 2




Lactate dehydrogenase




Monocarboxylic acid transporter 1


Malate dehydrogenase


Malic enzyme


Metabolomics-edited transcriptomic analysis


Metabolomics-edited transcriptomics and proteomics analysis


Mammalian target of rapamycin

N transporter

Neutral amino acid transporter




Poly(A)-binding protein




Pyruvate carboxylase




Pyruvate dehydrogenase


1,3-Phosphoinositide-dependent protein kinase






Phosphoenolpyruvate carboxykinase




Phosphoinositide-3 kinase


Pyruvate kinase


Protein kinase B


Protein kinase C






Pentose phosphate pathway


S6 protein kinase


Succinate dehydrogenase


Steroid-regulated-element binding protein


Trichloroacetic acid


Total correlation spectroscopy


5′-Tract of oligopyrimidine


Triosephosphate isomerase


Tuberous sclerosis component 2


13C labeled glucose


Uracil nucleotides



This work was supported in part by the National Cancer Institute grant # 1 R01 CA101199-01, NIH Grant Number RR018733 from the National Center for Research Resources, National Science Foundation EPSCoR grant # EPS-0447479, Kentucky Challenge for Excellence, and the Brown Foundation. We thank Dr. Laura Bandura and Ms. Vennila Arumugum for A549 cell culturing, sample processing, and extraction.



Metabolomics-edited transcriptomics analysis

Systems biology

Holistic and integrated analysis of biological processes as a system, not as individual parts


  1. 1.
    Griffiths JR, Stubbs M. Opportunities for studying cancer by metabolomics: preliminary observations on tumors deficient in hypoxia-inducible factor 1. Adv Enzyme Regul. 2003;43:67–76.PubMedGoogle Scholar
  2. 2.
    Watkins SM, et al. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. J Lipid Res. 2002;43(11):1809–17.PubMedGoogle Scholar
  3. 3.
    Hirai MY, et al. Integration of transcriptomics and metabolomics for understanding of global responses to nutritional stresses in Arabidopsis thaliana. Proc Natl Acad Sci U S A. 2004;101(27):10205–10.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Boros LG. Metabolic targeted therapy of cancer: current tracer technologies and future drug design strategies in the old metabolic network. Metabolomics. 2005;1(1):11–5.Google Scholar
  5. 5.
    Suzuki KT. Metabolomics of selenium: Se metabolites based on speciation studies. J Health Sci. 2005;51(2):107–14Google Scholar
  6. 6.
    Lafaye A, et al. Combined proteome and metabolite-profiling analyses reveal surprising insights into yeast sulfur metabolism. J Biol Chem. 2005;280(26):24723–30.PubMedGoogle Scholar
  7. 7.
    Smith MT, et al. Use of “Omic” technologies to study humans exposed to benzene. Chem Biol Interact. 2005;153:123–7.PubMedGoogle Scholar
  8. 8.
    Heijne WHM, et al. Profiles of metabolites and gene expression in rats with chemically induced hepatic necrosis. Toxicol Pathol. 2005;33(4):425–33.PubMedGoogle Scholar
  9. 9.
    Tohge T, et al. Functional genomics by integrated analysis of metabolome and transcriptome of Arabidopsis plants over-expressing an MYB transcription factor. Plant J. 2005;42(2):218–35.PubMedGoogle Scholar
  10. 10.
    Verhoeckx KCM, et al. Characterization of anti-inflammatory compounds using transcriptomics, proteomics, and metabolomics in combination with multivariate data analysis. Int Immunopharmacol. 2004;4(12):1499–5PubMedGoogle Scholar
  11. 11.
    Lenz EM, et al. Qualitative high field 1 H-NMR spectroscopy for the characterization of endogenous metabolites in earthworms with biochemical biomarker potential. Metabolomics. 2005;1(2):123–36.Google Scholar
  12. 12.
    Troy H, et al. Metabolic profiling of hypoxia-inducible factor-1β-deficient and wild type Hepa-1 cells: effects of hypoxia measured by 1H magnetic resonance spectroscopy. Metabolomics. 2005;1:1–11.Google Scholar
  13. 13.
    Whitehead T, Monzavi-Karbassi B, Kieber-Emmons T. 1H-NMR metabolomics analysis of sera differentiates between mammary tumor-bearing mice and healthy controls. Metabolomics. 2005;1:1–10.Google Scholar
  14. 14.
    Lutz NW. From metabolic to metabolomic NMR spectroscopy of apoptotic cells. Metabolomics. 2005;1:1–18.Google Scholar
  15. 15.
    Fan T, et al. Metabolomics-edited transcriptomics analysis of Se anticancer action in human lung cancer cells. Metabolomics J. 2005;1(4):325–39.Google Scholar
  16. 16.
    Rezzi S, et al. Application of 1H-NMR by metabolomics approach to exhaled breath condensate in childhood asthma. In: Abstracts of the 2nd scientific meeting of the metabolomics society, Boston, MA; 2006.Google Scholar
  17. 17.
    Yang L, et al. Metabolomic assays of the concentration and mass isotopomer distribution of gluconeogenic and citric acid cycle intermediates. Metabolomics. 2006;2(2):1573–3882.Google Scholar
  18. 18.
    Weljie AM, et al. Targeted profiling: quantitative analysis of H-1 NMR metabolomics data. Anal Chem. 2006;78(13):4430–42.PubMedGoogle Scholar
  19. 19.
    Fiehn O, et al. Metabolite profiling for plant functional genomics. Nat Biotechnol. 2000;18(11):1157–61.PubMedGoogle Scholar
  20. 20.
    Buchholz A, et al. Metabolomics: quantification of intracellular metabolite dynamics. Biomol Eng. 2002;19(1):5–15.PubMedGoogle Scholar
  21. 21.
    Baverel G, et al. Carbon 13 NMR spectroscopy: a powerful tool for studying renal metabolism. Biochimie. 2003;85(9):863–71.PubMedGoogle Scholar
  22. 22.
    Mesnard F, Ratcliffe RG. NMR analysis of plant nitrogen metabolism. Photosynth Res. 2005;83(2):163–80.PubMedGoogle Scholar
  23. 23.
    Robertson DG. Metabolomics in toxicology: a review. Toxicol Sci. 2005;85(2):809–22.PubMedGoogle Scholar
  24. 24.
    Whitehead TL, et al. H-1-NMR metabolomics analysis of zebrafish (Danio rerio) exposed to the environmentally-relevant EDC 17a-ethinylestradiol (EE2). In: Abstracts of papers of the American Chemical Society, Atlanta, GA; 2006. p. 231.Google Scholar
  25. 25.
    Lee WNP, Go VLW. Nutrient-gene interaction: tracer-based metabolomics. J Nutr. 2005;135(12):3027S–32.PubMedGoogle Scholar
  26. 26.
    Oresic M, et al. Serum metabolite patterns between birth and development of autoantibodies and overt type 1 diabetes: application of large-scale metabolomics to the Type 1 Diabetes Prediction and Prevention study (DIPP). Diabetologia. 2006;49:147.Google Scholar
  27. 27.
    Oresic M, Vidal-Puig A, Hanninen V. Metabolomic approaches to phenotype characterization and applications to complex diseases. Expert Rev Mol Diagn. 2006;6(4):575–85.PubMedGoogle Scholar
  28. 28.
    Chen HW, et al. Combining desorption electrospray ionization mass spectrometry and nuclear magnetic resonance for differential metabolomics without sample preparation. Rapid Commun Mass Spectrom. 2006;20(10):1577–84.PubMedGoogle Scholar
  29. 29.
    Weeks ME, et al. A parallel proteomic and metabolomic analysis of the hydrogen peroxide- and Sty1p-dependent stress response in Schizosaccharomyces pombe. Proteomics. 2006;6(9):2772–96.PubMedGoogle Scholar
  30. 30.
    Zimmermann D, et al. Determination of volatile products of human colon cell line metabolism by GC/MS analysis. Metabolomics. 2007;3(1):13–7.Google Scholar
  31. 31.
    Miccheli A, et al. Metabolic profiling by C-13-NMR spectroscopy: 1,2-C-13(2) glucose reveals a heterogeneous metabolism in human leukemia T cells. Biochimie. 2006;88(5):437–48.PubMedGoogle Scholar
  32. 32.
    Podrabsky JE, et al. Extreme anoxia tolerance in embryos of the annual killifish Austrofundulus limnaeus: insights from a metabolomics analysis. J Exp Biol. 2007;210(Pt 13):2253–66.PubMedGoogle Scholar
  33. 33.
    Morvan D, Demidem A. Metabolomics by proton nuclear magnetic resonance spectroscopy of the response to chloroethylnitrosourea reveals drug efficacy and tumor adaptive metabolic pathways. Cancer Res. 2007;67(5):2150–9.PubMedGoogle Scholar
  34. 34.
    Ohta D, Shibata D, Kanaya S. Metabolic profiling using Fourier-transform ion-cyclotron-resonance mass spectrometry. Anal Bioanal Chem. 2007;389(5):1469–75.PubMedGoogle Scholar
  35. 35.
    Oikawa A, et al. Clarification of pathway-specific inhibition by Fourier transform ion cyclotron resonance/mass spectrometry-based metabolic phenotyping studies. Plant Physiol. 2006;142(2):398–413.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Lane AN, Fan TW-M. Quantification and identification of isotopomer distributions of metabolites in crude cell extracts using 1 H TOCSY. Metabolomics. 2007;3:79–86.Google Scholar
  37. 37.
    Lindsley JE, Rutter J. Nutrient sensing and metabolic decisions. Comp Biochem Physiol B Biochem Mol Biol. 2004;139(4):543–59.PubMedGoogle Scholar
  38. 38.
    Frederich M, Balschi JA. The relationship between AMP-activated protein kinase activity and AMP concentration in the isolated perfused rat heart. J Biol Chem. 2002;277(3):1928–32.PubMedGoogle Scholar
  39. 39.
    Adams J, et al. Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site. Protein Sci. 2004;13(1):155–65.PubMedGoogle Scholar
  40. 40.
    Hawley SA, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003;2(4):28.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Zheng D, et al. Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J Appl Physiol. 2001;91(3):1073–83.PubMedGoogle Scholar
  42. 42.
    Yamauchi T, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288–95.PubMedGoogle Scholar
  43. 43.
    Jin Q, et al. Implication of AMP-activated protein kinase and Akt-regulated survivin in lung cancer chemopreventive activities of deguelin. Cancer Res. 2007;67(24):11630–9.PubMedGoogle Scholar
  44. 44.
    Carretero J, et al. Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Oncogene. 2007;26(11):1616–25.PubMedGoogle Scholar
  45. 45.
    Zhong D, et al. LKB1 mutation in large cell carcinoma of the lung. Lung Cancer. 2006;53(3):285–94.PubMedGoogle Scholar
  46. 46.
    Han S, Roman J. Rosiglitazone suppresses human lung carcinoma cell growth through PPARgamma-dependent and PPARgamma-independent signal pathways. Mol Cancer Ther. 2006;5(2):430–7.PubMedGoogle Scholar
  47. 47.
    Han S, Khuri FR, Roman J. Fibronectin stimulates non-small cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways. Cancer Res. 2006;66(1):315–23.PubMedGoogle Scholar
  48. 48.
    Mak BC, Yeung RS. The tuberous sclerosis complex genes in tumor development. Cancer Invest. 2004;22(4):588–603.PubMedGoogle Scholar
  49. 49.
    Ferré P, Azzout-Marniche D, Foufelle F. AMP-activated protein kinase and hepatic genes involved in glucose metabolism. Biochem Soc Trans. 2003;31(Pt 1):220–3.PubMedGoogle Scholar
  50. 50.
    Swinnen JV, et al. Androgens, lipogenesis and prostate cancer. J Steroid Biochem Mol Biol. 2004;92(4):273–9.PubMedGoogle Scholar
  51. 51.
    Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006;4(2):107–10.PubMedGoogle Scholar
  52. 52.
    Swinnen JV, et al. Mimicry of a cellular low energy status blocks tumor cell anabolism and suppresses the malignant phenotype. Cancer Res. 2005;65(6):2441–8.PubMedGoogle Scholar
  53. 53.
    Ravnskjaer K, et al. Glucose-induced repression of PPAR{alpha} gene expression in pancreatic {beta}-cells involves PP2A activation and AMPK inactivation. J Mol Endocrinol. 2006;36(2):289–99.PubMedGoogle Scholar
  54. 54.
    Reid ME, et al. Selenium supplementation and lung cancer incidence: an update of the nutritional prevention of cancer trial. Cancer Epidemiol Biomarkers Prev. 2002;V11(N11):1285–91.Google Scholar
  55. 55.
    Combs GFJ. Status of selenium in prostate cancer prevention. Br J Cancer. 2004;91:195–9.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Cohen V, Khuri FR. Chemoprevention of lung cancer. Curr Opin Pulm Med. 2004;10(4):279–83.PubMedGoogle Scholar
  57. 57.
    Patrick L. Selenium biochemistry and cancer: a review of the literature. Altern Med Rev. 2004;9(3):239–58.PubMedGoogle Scholar
  58. 58.
    Rayman MP. The importance of selenium to human health. Lancet. 2000;356(9225):233–41.PubMedGoogle Scholar
  59. 59.
    Reid ME, et al. A report of high-dose selenium supplementation: response and toxicities. J Trace Elem Med Biol. 2004;18(1):69–74.PubMedGoogle Scholar
  60. 60.
    Al-Taie OH, et al. Selenium supplementation enhances low selenium levels and stimulates glutathione peroxidase activity in peripheral blood and distal colon mucosa in past and present carriers of colon adenomas. Nutr Cancer. 2003;46(2):125–30.PubMedGoogle Scholar
  61. 61.
    Ganther HE. Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase. Carcinogenesis (Oxford). 1999;20(9):1657–66.Google Scholar
  62. 62.
    Arner ESJ, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000;267(20):6102–9.PubMedGoogle Scholar
  63. 63.
    Frenkel GD, Gong YH. Effect of selenite on tumor cell invasiveness. Cancer Lett. 1994;78(1–3):195–9.PubMedGoogle Scholar
  64. 64.
    Kryukov GV, et al. Characterization of mammalian selenoproteomes. Science. 2003;300(5624):1439–43.PubMedGoogle Scholar
  65. 65.
    Stadtman TC. Selenocysteine. Annu Rev Biochem. 1996;65:83–100.PubMedGoogle Scholar
  66. 66.
    Clark LC, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol. 1998;81(5):730–4.PubMedGoogle Scholar
  67. 67.
    Ip C, et al. In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. Cancer Res. 2000;60(11):2882–6.PubMedGoogle Scholar
  68. 68.
    Tanaka T, et al. Suppressing effects of dietary supplementation of the organoselenium 1,4-phenylenebis(methylene)selenocyanate and the Citrus antioxidant auraptene on lung metastasis of melanoma cells in mice. Cancer Res. 2000;60(14):3713–6.PubMedGoogle Scholar
  69. 69.
    Yan L, et al. Dietary supplementation of selenomethionine reduces metastasis of melanoma cells in mice. Anticancer Res. 1999;19(2A):1337–42.PubMedGoogle Scholar
  70. 70.
    Yan L, et al. Effect of dietary supplementation of selenite on pulmonary metastasis of melanoma cells in mice. Nutr Cancer. 1997;28(2):165–9.PubMedGoogle Scholar
  71. 71.
    Yoon SO, Kim MM, Chung AS. Inhibitory effect of selenite on invasion of HT1080 tumor cells. J Biol Chem. 2001;276(23):20085–92.PubMedGoogle Scholar
  72. 72.
    Ip C, et al. Chemical speciation influences comparative activity of selenium-enriched garlic and yeast in mammary cancer prevention. J Agric Food Chem. 2000;48(6):2062–70.PubMedGoogle Scholar
  73. 73.
    Li L, et al. Characteristics of selenazolidine prodrugs of selenocysteine: toxicity, selenium levels, and glutathione peroxidase induction in A/J mice. Life Sci. 2004;75(4):447–59.PubMedGoogle Scholar
  74. 74.
    Rudolf E, et al. Combined effect of sodium selenite and campthotecin on cervical carcinoma cells. Neoplasma (Bratislava). 2004;51(2):127–35.Google Scholar
  75. 75.
    Hu H, et al. Methylseleninic acid potentiates apoptosis induced by chemotherapeutic drugs in androgen-independent prostate cancer cells. Clin Cancer Res. 2005;11(6):2379–88.PubMedGoogle Scholar
  76. 76.
    Vadgama JV, et al. Effect of selenium in combination with Adriamycin or Taxol on several different cancer cells. Anticancer Res. 2000;20(3A):1391–4PubMedGoogle Scholar
  77. 77.
    Juliger S, et al. Chemosensitization of B-cell lymphomas by methylseleninic acid involves nuclear factor-kappaB inhibition and the rapid generation of other selenium species. Cancer Res. 2007;67(22):10984–92.PubMedGoogle Scholar
  78. 78.
    Li S, et al. Doxorubicin and selenium cooperatively induce fas signaling in the absence of Fas/Fas ligand interaction. Anticancer Res. 2007;27(5A):3075–82.PubMedGoogle Scholar
  79. 79.
    Santos RA, Takahashi CS. Anticlastogenic and antigenotoxic effects of selenomethionine on doxorubicin-induced damage in vitro in human lymphocytes. Food Chem Toxicol. 2008;46(2):671–7.PubMedGoogle Scholar
  80. 80.
    Li S, et al. Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates. Mol Cancer Ther. 2007;6(3):1031–8.PubMedGoogle Scholar
  81. 81.
    Zhang J, et al. Attenuating the toxicity of cisplatin by using selenosulfate with reduced risk of selenium toxicity as compared with selenite. Toxicol Appl Pharmacol. 2008;226(3):521–9.Google Scholar
  82. 82.
    Medina D, et al. Se-methylselenocysteine: a new compound for chemoprevention of breast cancer. Nutr Cancer. 2001;40(1):12–7.PubMedGoogle Scholar
  83. 83.
    Ma X, et al. Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase. J Biol Chem. 2001;276(27):24843–54.PubMedGoogle Scholar
  84. 84.
    Sinha R, et al. Methylseleninic acid, a potent growth inhibitor of synchronized mouse mammary epithelial tumor cells in vitro. Biochem Pharmacol. 2001;61(3):311–7.PubMedGoogle Scholar
  85. 85.
    Zhu Z, et al. Mechanisms of cell cycle arrest by methylseleninic acid. Cancer Res. 2002;62(1):156–64.PubMedGoogle Scholar
  86. 86.
    Tapiero H, Townsend DM, Tew KD. The antioxidant role of selenium and seleno-compounds. Biomed Pharmacother. 2003;57(3–4):134–44.PubMedGoogle Scholar
  87. 87.
    Stewart MS, et al. Selenium compounds have disparate abilities to impose oxidative stress and induce apoptosis. Free Radic Biol Med. 1999;26(1–2):42–8.PubMedGoogle Scholar
  88. 88.
    Shilo S, et al. Selenite sensitizes mitochondrial permeability transition pore opening in vitro and in vivo: a possible mechanism for chemo-protection. Biochem J. 2003;370(1):283–90.PubMedGoogle Scholar
  89. 89.
    Zheng Y, Zhong L, Shen X. Effect of selenium-supplement on the calcium signaling in human endothelial cells. J Cell Physiol. 2005;205(1):97–106.PubMedGoogle Scholar
  90. 90.
    Swede H, et al. Cell cycle arrest biomarkers in human lung cancer cells after treatment with selenium in culture. Cancer Epidemiol Biomarkers Prev. 2003;12(11):1248–52.PubMedGoogle Scholar
  91. 91.
    Becker K, et al. Thioredoxin reductase as a pathophysiological factor and drug target. Eur J Biochem. 2000;267(20):6118–25.PubMedGoogle Scholar
  92. 92.
    Huang LE, et al. Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem. 1996;271(50):32253–9.PubMedGoogle Scholar
  93. 93.
    Hayashi T, Ueno Y, Okamoto T. Oxidoreductive regulation of nuclear factor kappa B: involvement of a cellular reducing catalyst thioredoxin. J Biol Chem. 1993;268(15):11380–8.PubMedGoogle Scholar
  94. 94.
    Schenk H, et al. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-{kappa}B and AP-1. Proc Natl Acad Sci. 1994;91(5):1672–6.PubMedGoogle Scholar
  95. 95.
    Arredondo J, et al. A receptor-mediated mechanism of nicotine toxicity in oral keratinocytes. Lab Invest. 2001;81(12):1653–68.PubMedGoogle Scholar
  96. 96.
    Merrill GF, Dowell P, Pearson GD. The human p53 negative regulatory domain mediates inhibition of reporter gene transactivation in yeast lacking thioredoxin reductase. Cancer Res. 1999;59(13):3175–9.PubMedGoogle Scholar
  97. 97.
    Kaeck M, et al. Differential induction of growth arrest inducible genes by selenium compounds. Biochem Pharmacol. 1997;53(7):921–6.PubMedGoogle Scholar
  98. 98.
    Chae HZ, Kang SW, Rhee SG. Isoforms of mammalian peroxiredoxin that reduce peroxides in presence of thioredoxin. In: Packer L, (ed.) Methods in Enzymology: Oxidants and antioxidants, part B, Academic: San Diego; 1999. p. 219–26.Google Scholar
  99. 99.
    Saitoh M, et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998;17(9):2596–606.PubMedGoogle Scholar
  100. 100.
    Fan TWM, Higashi RM, Lane AN. Integrating metabolomics and transcriptomics for probing Se anticancer mechanisms. Drug Metab Rev. 2006;38(4):707–32.PubMedGoogle Scholar
  101. 101.
    Fan T, et al. Metabolomics-edited transcriptomics analysis of Se anticancer action in human lung cancer cells. Metabolomics J. 2006;1(4):325–39.Google Scholar
  102. 102.
    Vasta V, et al. Glutamine transport and enzymatic-activities involved in glutaminolysis in human platelets. Biochim Biophys Acta. 1995;1243(1):43–8.PubMedGoogle Scholar
  103. 103.
    Aledo JC, et al. Identification of two human glutaminase loci and tissue-specific expression of the two related genes. Mamm Genome. 2000;11(12):1107–10.PubMedGoogle Scholar
  104. 104.
    Carling D, Zammit VA, Hardie DG. A common bicyclic protein-kinase cascade inactivates the regulatory enzymes of fatty-acid and cholesterol-biosynthesis. FEBS Lett. 1987;223(2):217–22.PubMedGoogle Scholar
  105. 105.
    Farber SA, Slack BE, Blusztajn JK. Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: a model of the membrane defect of Alzheimer’s disease. FASEB J. 2000;14(14):2198–206.PubMedGoogle Scholar
  106. 106.
    Sanjuan MA, et al. Role of diacylglycerol kinase alpha in the attenuation of receptor signaling. J Cell Biol. 2001;153(1):207–20.PubMedGoogle Scholar
  107. 107.
    Fan TW-M, et al. Altered regulation of metabolic pathways in human lung cancer discerned by 13C stable isotope-resolved metabolomics (SIRM). Mol Cancer 2009;8:41–60.Google Scholar
  108. 108.
    Fan TWM, et al. Determination of metabolites by proton nmr and gc analysis for organic osmolytes in crude tissue extracts. Anal Biochem. 1993;214(1):260–71.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics (CREAM), and James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleUSA

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