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Depletion of deoxyribonucleoside triphosphate pools in tumor cells by nitric oxide
Béatrice Roy1, Olivier Guittet, Claire Beuneu
1UMR CNRS 8619, IBBMC, Université de Paris XI, F-91405 Orsay Cedex, France.
Abstract:
Nitric oxide displays pro- and anti-tumor activities, prompting further studies to better understand its precise role. Nitric oxide inhibits ribonucleotide reductase (RnR), the limiting enzyme for de novo dNTP synthesis. We report here the first detailed analysis of dNTP variations induced in tumor cells by NO. NO prodrugs induced a depletion in dNTP pools and an activation of the pyrimidine salvage pathway, as did hydroxyurea, the prototypic RnR inhibitor. In the presence of dipyridamole, which blocked salvaged dNTP synthesis, depletion of dNTP pools was also observed in tumor cells cocultured with macrophages expressing the high-output iNOS activity. This effect was rapid, reversible, blocked by NO scavengers, and cGMP independent. It was quantitatively correlated to iNOS activity. In the absence of dipyridamole, NO still induced a decrease in dATP concentration in tumor cells cocultured with macrophages, whereas surprisingly, concentrations of dCTP and dTTP expanded considerably, resulting in a strong imbalance in dNTP pools. NO prodrugs did not cause such an increase in pyrimidine dNTP, suggesting that pyrimidine nucleosides were released by NO-injured macrophages. Altered dNTP levels have been reported to promote mutagenesis and apoptosis. It is suggested that abnormal changes in dNTP pools in tumors might contribute to NO-dependent toxicity.
Insights
Nitric oxide (NO) alters cancer cell deoxyribonucleotide triphosphate (dNTP) pools by inhibiting synthesis and affecting salvage pathways. These dNTP pool changes may contribute to NO-driven tumor toxicity.
Area of Science:
- Biochemistry
- Cancer Biology
- Immunology
Background:
- Nitric oxide (NO) has complex roles in cancer, acting as both pro- and anti-tumorigenic.
- Deoxyribonucleotide triphosphate (dNTP) pools are critical for DNA synthesis and repair, and their dysregulation can impact cell fate.
Purpose of the Study:
- To investigate the precise effects of nitric oxide on deoxyribonucleotide triphosphate (dNTP) pools in tumor cells.
- To elucidate the mechanisms underlying NO-induced dNTP variations and their potential contribution to anti-tumor activity.
Main Methods:
- Analysis of dNTP pool variations in tumor cells treated with NO prodrugs or cocultured with macrophages expressing inducible nitric oxide synthase (iNOS).
- Utilized hydroxyurea (a ribonucleotide reductase inhibitor) and dipyridamole (a salvage pathway inhibitor) to dissect NO's effects.
- Quantified iNOS activity and assessed the impact of NO scavengers and cGMP.
Main Results:
- Nitric oxide prodrugs and iNOS activity led to dNTP pool depletion, similar to hydroxyurea.
- Inhibition of salvage pathways with dipyridamole still resulted in dNTP depletion in the presence of NO.
- Tumor cells cocultured with macrophages showed decreased dATP but increased dCTP and dTTP, creating a significant dNTP imbalance.
Conclusions:
- Nitric oxide profoundly impacts tumor cell dNTP pools through inhibition of synthesis and modulation of salvage pathways.
- The observed dNTP pool alterations, particularly the imbalance, may be a key mechanism underlying NO's anti-tumor effects.
- Understanding these NO-induced dNTP changes provides insights into cancer therapy and NO's complex role in tumorigenesis.
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