Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma

Joshua E. Lewis, Francesco Costantini, Jade Mims, Xiaofei Chen, Cristina M. Furdui, David A. Boothman, Melissa L. Kemp

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Aims: The purpose of this study was to investigate differential nicotinamide adenine dinucleotide phosphate, reduced (NADPH) production between radiation-sensitive and -resistant head and neck squamous cell carcinoma (HNSCC) cell lines and whether these differences are predictive of sensitivity to the chemotherapeutic β-lapachone. Results: We have developed a novel human genome-scale metabolic modeling platform that combines transcriptomic, kinetic, thermodynamic, and metabolite concentration data. Upon incorporation of this information into cell line-specific models, we observed that the radiation-resistant HNSCC model redistributed flux through several major NADPH-producing reactions. Upon RNA interference of canonical NADPH-producing genes, the metabolic network can further reroute flux through alternate NADPH biosynthesis pathways in a cell line-specific manner. Model predictions of perturbations in cellular NADPH production after gene knockdown match well with experimentally verified effects of β-lapachone treatment on NADPH/NADP+ ratio and cell viability. This computational approach accurately predicts HNSCC-specific oxidoreductase genes that differentially affect cell viability between radiation-responsive and radiation-resistant cancer cells upon β-lapachone treatment. Innovation: Quantitative genome-scale metabolic models that incorporate multiple levels of biological data are applied to provide accurate predictions of responses to a NADPH-dependent redox cycling chemotherapeutic drug under a variety of perturbations. Conclusion: Our modeling approach suggests differences in metabolism and β-lapachone redox cycling that underlie phenotypic differences in radiation-sensitive and -resistant cancer cells. This approach can be extended to investigate the synergistic action of NAD(P)H: quinone oxidoreductase 1 bioactivatable drugs and radiation therapy. Antioxid. Redox Signal. 29, 937-952.

Original languageEnglish (US)
Pages (from-to)937-952
Number of pages16
JournalAntioxidants and Redox Signaling
Volume29
Issue number10
DOIs
StatePublished - Oct 1 2018

Keywords

  • b-lapachone
  • flux balance analysis
  • head and neck cancer
  • NADPH
  • redox cycling

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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    Lewis, J. E., Costantini, F., Mims, J., Chen, X., Furdui, C. M., Boothman, D. A., & Kemp, M. L. (2018). Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma. Antioxidants and Redox Signaling, 29(10), 937-952. https://doi.org/10.1089/ars.2017.7048