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Published on: May 21, 2020
Multimodal control of Cdc25A by nitrosative stress
1Department of Pharmacology and Chemical Biology and University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Cancer Research
|September 17, 2008
Summary
Nitric oxide (NO) and related species rapidly inhibit Cdc25A phosphatase activity and decrease its protein levels. This suppression, mediated by nitrosative stress and eukaryotic initiation factor 2alpha (eIF2alpha), primes cancer cells for apoptosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Cdc25A is crucial for cell cycle progression and is overexpressed in many human cancers, exhibiting oncogenic and antiapoptotic properties.
- While reactive oxygen species regulate Cdc25A, the effects of nitric oxide (NO) and its derived reactive species on Cdc25A are not well understood.
Purpose of the Study:
- To investigate the mechanisms by which NO and nitrosative stress regulate Cdc25A.
- To determine the functional consequences of Cdc25A suppression by nitrosative stress in cancer cells.
Main Methods:
- In vitro treatment with S-nitrosocysteine ethyl ester (SNCEE) to induce nitrosative stress.
- Analysis of Cdc25A phosphatase activity, protein levels, and translation.
- Investigation of the role of eukaryotic initiation factor 2alpha (eIF2alpha) and apoptosis signal-regulating kinase-1 (ASK-1) signaling.
Main Results:
- SNCEE directly inhibited Cdc25A phosphatase activity in vitro.
- SNCEE and inducible nitric oxide synthase (iNOS)-derived NO decreased Cdc25A protein levels in cancer cells.
- Cdc25A suppression occurred via inhibition of eIF2alpha-mediated translation, not altered protein stability.
- Nitrosative stress reduced Cdc25A binding to ASK-1, sensitizing cells to chemotherapy-induced apoptosis.
Conclusions:
- Novel NO-dependent enzymatic and translational mechanisms control Cdc25A activity and expression.
- Suppression of Cdc25A by nitrosative stress plays a role in NO-mediated apoptotic signaling.
- Cdc25A is implicated as a mediator in NO-dependent apoptosis pathways.
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