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

3 Citations (Scopus)

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

Fingerprint

NADP
Genes
Genome
Cells
Radiation
Oxidation-Reduction
Cell Line
Cell Survival
Oxidoreductases
Fluxes
Gene Knockdown Techniques
Drug therapy
Carcinoma, squamous cell of head and neck
Epithelial Cells
Gene Regulatory Networks
Biosynthesis
Radiotherapy
Human Genome
Metabolites
RNA Interference

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

Cite this

Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma. / Lewis, Joshua E.; Costantini, Francesco; Mims, Jade; Chen, Xiaofei; Furdui, Cristina M.; Boothman, David A.; Kemp, Melissa L.

In: Antioxidants and Redox Signaling, Vol. 29, No. 10, 01.10.2018, p. 937-952.

Research output: Contribution to journalArticle

Lewis, Joshua E. ; Costantini, Francesco ; Mims, Jade ; Chen, Xiaofei ; Furdui, Cristina M. ; Boothman, David A. ; Kemp, Melissa L. / Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma. In: Antioxidants and Redox Signaling. 2018 ; Vol. 29, No. 10. pp. 937-952.
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