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S-Glutathionylation and S-Nitrosylation as Modulators of Redox-Dependent Processes in Cancer Cell
Elena V Kalinina1, Maria D Novichkova2
1RUDN University, Moscow, 117198, Russia. kalinina-ev@rudn.ru.
Abstract:
Development of oxidative/nitrosative stress associated with the activation of oncogenic pathways results from the increase in the generation of reactive oxygen and nitrogen species (ROS/RNS) in tumor cells, where they can have a dual effect. At high concentrations, ROS/RNS cause cell death and limit tumor growth at certain phases of its development, while their low amounts promote oxidative/nitrosative modifications of key redox-dependent residues in regulatory proteins. The reversibility of such modifications as S-glutathionylation and S-nitrosylation that proceed through the electrophilic attack of ROS/RNS on nucleophilic Cys residues ensures the redox-dependent switch in the activity of signaling proteins, as well as the ability of these compounds to control cell proliferation and programmed cell death. The content of S-glutathionylated and S-nitrosylated proteins is controlled by the balance between S-glutathionylation/deglutathionylation and S-nitrosylation/denitrosylation, respectively, and depends on the cellular redox status. The extent of S-glutathionylation and S-nitrosylation of protein targets and their ratio largely determine the status and direction of signaling pathways in cancer cells. The review discusses the features of S-glutathionylation and S-nitrosylation reactions and systems that control them in cancer cells, as well as their relationship with redox-dependent processes and tumor growth.
Insights
Reactive oxygen and nitrogen species (ROS/RNS) impact cancer cell signaling. Their reversible modifications of proteins control cell proliferation and programmed cell death, influencing tumor growth.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Oxidative and nitrosative stress are hallmarks of cancer, driven by reactive oxygen and nitrogen species (ROS/RNS).
- ROS/RNS exhibit dual roles in tumors: high levels induce cell death, while low levels modulate protein activity.
- Redox-dependent protein modifications, like S-glutathionylation and S-nitrosylation, are crucial for cell signaling.
Purpose of the Study:
- To review the mechanisms of S-glutathionylation and S-nitrosylation in cancer cells.
- To explore how these modifications regulate signaling pathways controlling proliferation and cell death.
- To discuss the relationship between redox balance, protein modification, and tumor progression.
Main Methods:
- Literature review focusing on redox signaling in cancer.
- Analysis of biochemical pathways involving ROS/RNS and protein cysteine residues.
- Examination of regulatory systems controlling protein S-glutathionylation and S-nitrosylation.
Main Results:
- S-glutathionylation and S-nitrosylation are reversible modifications of cysteine residues by ROS/RNS.
- These modifications act as redox switches, altering signaling protein activity.
- The balance of protein glutathionylation/denitrosylation and nitrosylation/denitrosylation dictates cellular redox status and signaling outcomes.
- The extent and ratio of these modifications influence cancer cell proliferation and programmed cell death.
Conclusions:
- S-glutathionylation and S-nitrosylation are key redox-dependent regulatory mechanisms in cancer.
- These reversible protein modifications play a critical role in controlling cancer cell signaling, proliferation, and survival.
- Understanding these pathways is vital for deciphering tumor growth dynamics and developing targeted therapies.
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