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A Model for Perineural Invasion in Head and Neck Squamous Cell Carcinoma
Published on: January 5, 2017
Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma
Joshua E Lewis1, Francesco Costantini2, Jade Mims3
11 The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University , Atlanta, Georgia .
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.
Insights
This study reveals that differences in nicotinamide adenine dinucleotide phosphate, reduced (NADPH) production predict head and neck squamous cell carcinoma (HNSCC) cell sensitivity to the chemotherapeutic β-lapachone. Computational modeling accurately predicted treatment responses and identified key genes.
Area of Science:
- Metabolic modeling
- Cancer biology
- Pharmacology
Background:
- Head and neck squamous cell carcinoma (HNSCC) exhibits varying sensitivity to radiation and chemotherapy.
- Nicotinamide adenine dinucleotide phosphate, reduced (NADPH) plays a critical role in cellular redox balance and drug metabolism.
Purpose of the Study:
- To investigate differential NADPH production in radiation-sensitive versus -resistant HNSCC cell lines.
- To determine if NADPH production differences predict sensitivity to the chemotherapeutic agent β-lapachone.
Main Methods:
- Development of a novel human genome-scale metabolic modeling platform integrating transcriptomic, kinetic, thermodynamic, and metabolite concentration data.
- Application of cell line-specific models to predict metabolic flux redistribution and responses to gene knockdown.
- Experimental validation of model predictions using β-lapachone treatment and assessment of NADPH/NADP+ ratio and cell viability.
Main Results:
- Radiation-resistant HNSCC models showed flux redistribution in major NADPH-producing reactions.
- Metabolic networks rerouted flux through alternate NADPH biosynthesis pathways upon gene knockdown.
- Computational predictions of NADPH perturbations and β-lapachone effects on cell viability were experimentally verified.
Conclusions:
- Metabolic modeling accurately predicts HNSCC cell response to β-lapachone based on NADPH production.
- Differences in metabolism and β-lapachone redox cycling underlie radiation sensitivity phenotypes in HNSCC.
- The modeling approach can be extended to investigate synergistic therapies involving NAD(P)H: quinone oxidoreductase 1 bioactivatable drugs and radiation.
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