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Journal of Biomolecular NMR

, Volume 49, Issue 3–4, pp 185–193 | Cite as

1H NMR metabolomics identification of markers of hypoxia-induced metabolic shifts in a breast cancer model system

  • Aalim M. Weljie
  • Alla Bondareva
  • Ping Zang
  • Frank R. Jirik
Article

Abstract

Hypoxia can promote invasive behavior in cancer cells and alters the response to therapeutic intervention as a result of changes in the expression many genes, including genes involved in intermediary metabolism. Although metabolomics technologies are capable of simultaneously measuring a wide range of metabolites in an untargeted manner, these methods have been relatively under utilized in the study of cancer cell responses to hypoxia. Thus, 1H NMR metabolomics was used to examine the effects of hypoxia in the MDA-MB-231 human breast cancer cell line, both in vitro and in vivo. Cell cultures were compared with respect to their metabolic responses during growth under either hypoxic (1% O2) or normoxic conditions. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to identify a set of metabolites that were responsive to hypoxia. Via intracardiac administration, MDA-MB-231 cells were also used to generate widespread metastatic disease in immuno-compromised mice. Serum metabolite analysis was conducted to compare animals with and without a large tumor burden. Intriguingly, using a cross-plot of the OPLS loadings, both the in vitro and in vivo samples yielded a subset of metabolites that were significantly altered by hypoxia. These included primarily energy metabolites and amino acids, indicative of known alterations in energy metabolism, and possibly protein synthesis or catabolism. The results suggest that the metabolite pattern identified might prove useful as a marker for intra-tumoral hypoxia.

Keywords

Metabolomics 1H NMR spectroscopy Hypoxia Glycolysis Breast cancer Chemometrics OPLS-DA Tumor xenograft 

Abbreviations

HIF

Hypoxia inducible factor

MCT

Monocarboxylate transporter

MDA-MB-231-Luc2

MDA-MB-231 Luciferase

OPLS-DA

Orthogonal partial least squares discriminant analysis

PCA

Principal component analysis

VIP

Variable influence on projection

Notes

Acknowledgments

The Metabolomics Research Centre at the University of Calgary is supported by funding from Alberta Health Services (AHS)/The Alberta Cancer Foundation (ACF). The studies were also supported in part by a translational grant from the AHS/ACF (to F.R.J.); F.R.J was the recipient of a Canada Research Chairs award.

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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Aalim M. Weljie
    • 1
  • Alla Bondareva
    • 2
    • 3
  • Ping Zang
    • 4
  • Frank R. Jirik
    • 2
  1. 1.Department of Biological SciencesUniversity of CalgaryCalgaryCanada
  2. 2.Department of Biochemistry and Molecular BiologyMcCaig Institute for Bone and Joint HealthCalgaryCanada
  3. 3.Department of Comparative Biology and Experimental MedicineCalgaryCanada
  4. 4.Department of ChemistryUniversity of CalgaryCalgaryCanada

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