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Metabolomics-edited transcriptomics analysis of Se anticancer action in human lung cancer cells

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Transcriptomic analysis is an essential tool for systems biology but it has been stymied by a lack of global understanding of genomic functions, resulting in the inability to link functionally disparate gene expression events. Using the anticancer agent selenite and human lung cancer A549 cells as a model system, we demonstrate that these difficulties can be overcome by a progressive approach which harnesses the emerging power of metabolomics for transcriptomic analysis. We have named the approach Metabolomics-edited transcriptomic analysis (META). The main analytical engine was 13C isotopomer profiling using a combination of multi-nuclear 2-D NMR and GC-MS techniques. Using 13C-glucose as a tracer, multiple disruptions to the central metabolic network in A549 cells induced by selenite were defined. META was then achieved by coupling the metabolic dysfunctions to altered gene expression profiles to: (1) provide new insights into the regulatory network underlying the metabolic dysfunctions; (2) enable the assembly of disparate gene expression events into functional pathways that was not feasible by transcriptomic analysis alone. This was illustrated in particular by the connection of mitochondrial dysfunctions to perturbed lipid metabolism via the AMP-AMPK pathway. Thus, META generated both extensive and highly specific working hypotheses for further validation, thereby accelerating the resolution of complex biological problems such as the anticancer mechanism of selenite.

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Abbreviations

1H–13C HMBC:

1H–13C heteronuclear multiple bond correlation spectroscopy

1H–13C HSQC:

1H–13C heteronuclear single quantum coherence spectroscopy

2-D 1H TOCSY:

two dimensional 1H total correlation spectroscopy

[U−13C]-glucose:

uniformly 13C-labeled glucose

GC:

gas chromatography

META:

metabolomics-edited transcriptomic analysis

MSn:

mass spectrometry to the nth dimension

MTBSTFA:

N-methyl-N-[tert-butyldimethylsilyl]trifluoroacetamide

NMR:

nuclear magnetic resonance spectroscopy

P-choline or PC:

phosphorylcholine

PDA:

photodiode array

TCA:

trichloroacetic acid

References

  • Aledo J.C., Gomez-Fabre P.M., Olalla L., Marquez J. (2000). Mammalian Genome. 11:1107–1110

    Article  PubMed  Google Scholar 

  • Arner E.S.J., Holmgren A. (2000). European Journal of Biochemistry 267:6102–6109

    Article  PubMed  Google Scholar 

  • Bandura L., Drukala J., Wolnicka-Glubisz A., Bjornstedt M., Korohoda W. (2005). Biochemistry and cell biology. 83:196–211

    Article  PubMed  Google Scholar 

  • Becker K., Gromer S., Schirmer R.H., Mueller S. (2000). Eur. J. Biochem. 267:6118–6125

    Article  PubMed  Google Scholar 

  • Bonneau M.J., Poulin R. (2000). Experimental Cell Research. 259:23–34

    Article  PubMed  Google Scholar 

  • Brindle K.M., Radda G.K. (1987). Biochimica et biophysica acta. 928:45–55

    Article  PubMed  Google Scholar 

  • Carling D., Zammit V.A., Hardie D.G. (1987). Febs Letters 223: 217–222

    Article  PubMed  Google Scholar 

  • Clark L.C., Dalkin B., Krongrad A., Combs G.F. Jr., Turnbull B.W., Slate E.H., Witherington R., Herlong J.H., Janosko E., Carpenter D., Borosso C., Falk S., Rounder J. (1998). British Journal of Urology. 81:730–734

    PubMed  Google Scholar 

  • Fan T. W.-M. (1996) Progress in Nuclear Magnetic Resonance Spectroscopy 28:161–219

    Google Scholar 

  • Fan, T. W.-M. (1996) in Shachar-Hill, Y. and Pfeffer, P. E. (Eds), Nuclear Magnetic Resonance in plant biology, Vol. 16. American Society of Plant Physiologists, Rockville, Maryland, pp. 181–254.

  • Fan T.W.M., Higashi R.M., Lane A.N. (1992). Biochimica et Biophysica Acta 1135:44–49

    Article  PubMed  Google Scholar 

  • Fan T.W.M., Colmer T.D., Lane A.N., Higashi R.M. (1993). Analytical Biochemistry. 214:260–271

    Article  PubMed  Google Scholar 

  • Fan T.W.M., Higashi R.M., Frenkiel T.A., Lane A.N. (1997) Journal of Experimental Botany 48:1655–1666

    Article  Google Scholar 

  • Fan T.W.M., Lane A.N., Higashi R.M. (2003). Russian Journal of Plant Physiology. 50:787–793

    Article  Google Scholar 

  • Fan T.W.-M., Lane A.N., Higashi R.M. (2004). asdasd. Current Opnion in Molecular Therapeutics 6:584–592

    PubMed  Google Scholar 

  • Farber S.A., Slack B.E., Blusztajn J.K. (2000). FASEB J. 14: 2198–2206

    Article  PubMed  Google Scholar 

  • Gadian D.G. (1995). NMR and its applications to living systems. Oxford University Press, Oxford U.K.

    Google Scholar 

  • Ganther H.E. (1999). Carcinogenesis (Oxford) 20:1657–1666

    Article  Google Scholar 

  • Gradwell M.J., Fan T.W.M., Lane A.N. (1998). Analytical Biochemistry 263:139–149

    Article  PubMed  Google Scholar 

  • Heijne W.H.M., Lamers R., van Bladeren P.J., Groten J.P., van Nesselrooij J.H.J., van Ommen B. (2005). Toxicologic Pathology. 33:425–433

    PubMed  Google Scholar 

  • Hirai M.Y., Yano M., Goodenowe D.B., Kanaya S., Kimura T., Awazuhara M., Arita M., Fujiwara T., Saito K. (2004). PNAS. 101:10205–10210

    Article  PubMed  Google Scholar 

  • Huang L.E., Arany Z., Livingston D.M., Bunn H.F. (1996). J. Biol. Chem. 271:32253–32259

    Article  PubMed  Google Scholar 

  • Ip C., Thompson H.J., Zhu Z., Ganther H.E. (2000). Cancer Research. 60:2882–2886

    PubMed  Google Scholar 

  • Lee W.-N.P., Boros L.G., Puigjaner J., Bassilian S., Lim S. Cascante, M. (1998). Am J Physiol Endocrinol Metab. 274:E843–851

    Google Scholar 

  • Lindsley J.E., Rutter J. (2004). Comparative Biochemistry and Physiology B-Biochemistry & Molecular Biology. 139:543–559

    Article  Google Scholar 

  • Lu D., Mulder H., Zhao P., Burgess S.C., Jensen M.V., Kamzolova S., Newgard C.B., Sherry A.D. (2002). Proceedings of the National Academy of Sciences of the United States of America 99:2708–2713

    Article  PubMed  Google Scholar 

  • Merrill G.F., Dowell P., Pearson G.D. (1999). Cancer Research 59:3175–3179

    PubMed  Google Scholar 

  • Mustacich D., Powis G. (2000). Biochemical Journal. 346:1–8

    Article  PubMed  Google Scholar 

  • Persson, L., Dartsch, C., Wallstrom, E. L. and Svensson, F. (1999) in Bardocz, S. and White, C. (Eds), Polyamines in Health and Nutrition, Kluwer Academic Publishers, Boston, pp. 27–34.

  • Sanjuan M.A., Jones D.R., Izquierdo M., Merida I. (2001). J. Cell Biol. 153:207–220

    Article  PubMed  Google Scholar 

  • Sasada T., Nakamura H., Ueda S., Sato N., Kitaoka Y., Gon Y., Takabayashi A., Spyrou G., Holmgren A., Yodoi J. (1999). Free Radical Biology & Medicine. 27:504–514

    Article  PubMed  Google Scholar 

  • Schenk H., Klein M., Erdbrugger W., Droge W., Schulze-Osthoff K. (1994). PNAS. 91:1672–1676

    PubMed  Google Scholar 

  • Schrauzer G.N. (2002). Journal of Nutrition 132:1653–1656

    Google Scholar 

  • Stadtman, T. C. (2000) in Reactive Oxygen Species: From Radiation to Molecular Biology, Vol. 899. New york Acad sciences, New York, pp. 399–402.

  • Tanaka T., Kohno H., Murakami M., Kagami S., El-Bayoumy K. (2000). Cancer Research. 60:3713–3716

    PubMed  Google Scholar 

  • Vasta V., Meacci E., Farnararo M., Bruni P. (1995). Biochimica Et Biophysica Acta-General Subjects. 1243:43–48

    Article  Google Scholar 

  • Verhoeckx K.C.M., Bijlsma S., Jespersen S., Ramaker R., Verheij E. R., Witkamp R.F., van der Greef J., Rodenburg R.J.T. (2004). International Immunopharmacology. 4:1499–1514

    Article  PubMed  Google Scholar 

  • Yan L., Yee J.A., McGuire M.H., Graef, G.L. (1997) . Nutrition & Cancer-An International Journal. 28:165–169

    PubMed  Google Scholar 

  • Yan L., Yee J.A., Li D.H., McGuire M.H., Graef G.L. (1999). Anticancer Research. 19:1337–1342

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by NCI Grant 1 R01 CA101199-01, the JG Brown Foundation for the NMR facility and Microarray facility of the JG Brown Cancer Center and NSF EPSCoR Grant EPS-0132295 for the 18.8 T NMR spectrometer (to R.J. Wittebort) and NSF EPSCoR grant EPS-0447479 (to T.W.-M. Fan). ANL thanks the Kentucky Challenge for Excellence for support. We also thank Ms. Anna Tchernatynskaia for performing the HPLC analysis of nucleotides and Dr. Sabine Waigel for assistance in microarray data analysis.

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Authors and Affiliations

  1. Department of Chemistry, University of Louisville, 2320 S. Brook St., Louisville, KY, 40208, USA

    Teresa W. M. Fan & Laura L. Bandura

  2. J.G. Brown Cancer Center, University of Louisville, 529 S. Jackson St., Louisville, KY, 40202, USA

    Teresa W. M. Fan & Andrew N. Lane

  3. John Muir Institute for the Environment, Center for Health and Environment, University of California, One Shields Ave., Davis, CA, 95616, USA

    Richard M. Higashi

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  1. Teresa W. M. Fan
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  2. Laura L. Bandura
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Correspondence to Teresa W. M. Fan.

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Fan, T.W.M., Bandura, L.L., Higashi, R.M. et al. Metabolomics-edited transcriptomics analysis of Se anticancer action in human lung cancer cells. Metabolomics 1, 325–339 (2005). https://doi.org/10.1007/s11306-005-0012-0

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  • DOI: https://doi.org/10.1007/s11306-005-0012-0

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