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Published on: February 25, 2016
A cohort of supporting metabolic enzymes is coinduced with nitric oxide synthase in human tumor cell lines
A K Nussler1, Z Z Liu, K Hatakeyama
1Department of General Surgery, University of Ulm, Germany.
Abstract:
Although nitric oxide (NO) has cytotoxic activity against certain tumor cell lines, some human tumor cell lines can themselves produce NO by expressing the inducible isoform of NO synthase (iNOS). As rates of cellular NO synthesis play a major role in determining whether NO has cytotoxic or cytoprotective effects at anatomic sites of NO production, identification of cellular processes which regulate rates of NO synthesis by iNOS is important for understanding the role of NO in tumor cell biology. This study demonstrates that argininosuccinate synthetase and GTP-cyclohydrolase-I, which catalyze rate-limiting steps in the synthesis of iNOS substrate (arginine) and cofactor (tetrahydrobiopterin), respectively, are coinduced with iNOS expression in two human tumor cell lines. These results indicate that coinduction of these supporting metabolic pathways helps to maximize cellular NO synthesis by iNOS in human tumor cells, suggesting that these pathways might be useful targets for pharmacologic intervention in NO-producing human tumor cells.
Insights
Human tumor cells can produce nitric oxide (NO) via inducible NO synthase (iNOS). Supporting metabolic pathways are coinduced with iNOS, maximizing NO synthesis and offering potential therapeutic targets.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Nitric oxide (NO) exhibits dual roles, acting as cytotoxic or cytoprotective agent.
- Tumor cells can synthesize NO through inducible NO synthase (iNOS).
- Understanding NO synthesis regulation in tumors is crucial for cancer biology.
Purpose of the Study:
- To investigate cellular processes regulating NO synthesis by iNOS in human tumor cells.
- To identify metabolic pathways supporting iNOS activity.
Main Methods:
- Analysis of iNOS expression in human tumor cell lines.
- Assessment of argininosuccinate synthetase and GTP-cyclohydrolase-I activity.
- Evaluation of coinduction patterns with iNOS.
Main Results:
- iNOS expression was observed in two human tumor cell lines.
- Argininosuccinate synthetase and GTP-cyclohydrolase-I were coinduced with iNOS.
- Coinduction of these enzymes maximizes NO synthesis by iNOS.
Conclusions:
- Coordinated upregulation of metabolic pathways supports maximal NO production in iNOS-expressing tumor cells.
- These pathways represent potential targets for pharmacological intervention in cancer therapy.
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