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Volume 2 Supplement 1

Metabolism, Diet and Disease 2014: Cancer and metabolism

1H Nuclear magnetic resonance based targeted profiling of metabolic responses induced by DNA damaging agents and PARP inhibition in MCF-7 cells

Cancer & Metabolism volume 2, Article number: P8 (2014) Cite this article

Background

Maintaining DNA integrity is essential for cell survival and proper functioning. Therefore, many cancer therapies, including radiotherapy and several chemotherapeutic drugs, induce damage to the DNA leading to genomic instability [1]. There are several DNA damage responses (DDRs) which can be activated depending on the type and the extent of DNA damage [1]. These responses involve detection of the damage by several proteins including, poly (ADP-ribose) polymerase (PARP), which can directly or indirectly affect metabolism [1].

Materials and methods

We have used NMR based targeted profiling [2] to compare different DNA damage responses and study the effect of PARP inhibition on metabolism in the MCF-7 cell line. Methyl methanesulphonate (MMS), cisplatin, γ-radiation, and zeocin; were used to trigger different DDRs. ABT-888 (Veliparib) was used to study the effect of PARP inhibition on metabolism, both as a single agent and in combination with DNA damaging agents.

Results

We observed several similarities in the metabolic responses caused by different DDRs and also identified specific metabolite markers on treatment with these DNA damaging agents. PARP inhibition restored most of the metabolic changes observed in MMS-treated cells suggesting that the metabolic response observed after MMS treatment may be predominantly due to PARP activation.

Conclusions

In this study, we identified several similarities and differences in metabolic responses induced by different types of DDRs, which suggests the redirection of metabolic fluxes in a DNA damage-dependent manner. We also observed that recruitment of PARP during the DNA repair process can lead to widespread metabolic changes by observing the effect of PARP inhibition in MMS-treated cells. These results have identified novel metabolic responses in cancer cells following DNA damage and on inhibiting activity of proteins involved in DNA repair processes.

References

  1. Lord CJ, Ashworth A: The DNA damage response and cancer therapy. Nature. 2012, 481: 287-294. 10.1038/nature10760.

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  2. Weljie AM, Newton J, Mercier P, Carlson E, Slupsky CM: Targeted profiling: quantitative analysis of 1H NMR metabolomics data. Anal Chem. 2006, 78: 4430-4442. 10.1021/ac060209g.

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Acknowledgements

This work was supported by the National Institute of Health grant R01CA164492. The authors are grateful to Dr. L. Clos and Dr. J. Markley for assistance with NMR facility.

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Authors and Affiliations

  1. Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA

    Vijesh Bhute & Sean Palecek

  2. Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

    Daniel Beard

  3. Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL, USA

    Stephen Kron

Authors
  1. Vijesh Bhute
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  2. Daniel Beard
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  3. Stephen Kron
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  4. Sean Palecek
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Bhute, V., Beard, D., Kron, S. et al. 1H Nuclear magnetic resonance based targeted profiling of metabolic responses induced by DNA damaging agents and PARP inhibition in MCF-7 cells. Cancer Metab 2 (Suppl 1), P8 (2014). https://doi.org/10.1186/2049-3002-2-S1-P8

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  • DOI: https://doi.org/10.1186/2049-3002-2-S1-P8

Keywords

  • Metabolic Response
  • Metabolic Flux
  • PARP Inhibition
  • PARP Activation
  • Specific Metabolite

Cancer & Metabolism

ISSN: 2049-3002