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Tumor Suppressor Roles of the Denitrosylase GSNOR
Salvatore Rizza1, Giuseppe Filomeni2
1Redox Signaling and Oxidative Stress Research Group, Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark.
Abstract:
Nitric oxide (NO) is a gaseous pleiotropic molecule that can both induce irreversible oxidative damages and modulate physiological signal transductions by transient protein modifications, the most important of which is the S-nitrosylation of cysteine residues. Being noxious and healthy, the role of NO in cancer is seemingly contradictory, as at low concentrations it mediates tumor growth and proliferation whereas at high concentrations it promotes apoptosis and cancer growth inhibition. However, it is becoming evident that when endogenously produced, such as upon inducible nitric oxide synthase (NOS) activation, NO acts to sustain tumorigenesis. Similarly, although less explored, defects and deficiency in the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR) have been associated with the development and malignancy of liver and breast cancers, suggesting a primary role for NO signaling-that is, S-nitrosylation, being deeply involved in neoplastic transformation and progression. In this review, we summarize past and recent evidence on the role of S-nitrosylation and GSNOR in different processes that contribute to cell transformation when deregulated, such as DNA damage repair, energetic metabolism, and cell death. We also outline possible S-nitrosylation-targeted proteins that might contribute to tumorigenesis, and, finally, we speculate on the role of GSNOR in regulating the oncogenic effects induced downstream.
Insights
Nitric oxide (NO) signaling, specifically S-nitrosylation, plays a dual role in cancer. Dysregulation of NO and S-nitrosoglutathione reductase (GSNOR) contributes to tumor development and progression.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research
- Cellular Signaling
Background:
- Nitric oxide (NO) is a pleiotropic molecule with complex roles in physiology and disease.
- NO exhibits dual effects in cancer, promoting growth at low concentrations and inhibiting it at high concentrations.
- Endogenous NO production and impaired denitrosylation by S-nitrosoglutathione reductase (GSNOR) are linked to tumorigenesis.
Purpose of the Study:
- To review the multifaceted role of S-nitrosylation and GSNOR in cancer.
- To explore how deregulated S-nitrosylation impacts key cellular processes like DNA repair, metabolism, and cell death.
- To identify potential S-nitrosylation targets contributing to cancer and the role of GSNOR in regulating these effects.
Main Methods:
- Literature review of existing evidence on nitric oxide, S-nitrosylation, and GSNOR in cancer.
- Analysis of studies investigating the impact of S-nitrosylation on cellular processes.
- Discussion of potential protein targets and GSNOR's regulatory role.
Main Results:
- S-nitrosylation is deeply implicated in neoplastic transformation and cancer progression.
- Defects in GSNOR are associated with liver and breast cancer development and malignancy.
- Deregulation of S-nitrosylation affects DNA repair, cellular metabolism, and cell death pathways.
Conclusions:
- Nitric oxide signaling, particularly S-nitrosylation, is a critical factor in cancer development.
- GSNOR plays a significant role in preventing oncogenic transformation by regulating S-nitrosylation.
- Targeting S-nitrosylation pathways presents potential therapeutic strategies for cancer treatment.
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