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STAT3 Regulation By S-Nitrosylation: Implication In Cancer.
Inderjit Singh1, Jinsu Kim1, Avtar K Singh1
1Departments of Pediatrics, Pathology and Laboratory Medicine and Radiation Oncology. Medical University of South Carolina, Charleston, SC, USA.
Redox Biology
|February 7, 2017
Summary
S-nitrosoglutathione (GSNO) inhibits Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway activation by S-nitrosylating STAT3 at Cys259. This inhibition reduces cancer cell proliferation and tumor growth, suggesting GSNO as a therapeutic agent.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- The Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway is crucial in cellular signaling.
- STAT3 activation is implicated in tumor progression and metastasis.
- Redox modifications, including S-nitrosylation, play regulatory roles in cellular pathways.
Purpose of the Study:
- To investigate the S-nitrosylation-based regulation of the JAK2/STAT3 pathway.
- To determine the role of S-nitrosoglutathione (GSNO) in STAT3 activation and its therapeutic potential in head and neck squamous cell carcinoma (HNSCC).
Main Methods:
- Assessed redox-dependent modifications of STAT3 in microglia.
- Utilized cell-free kinase assays with purified JAK2 and STAT3.
- Investigated the effect of GSNO on STAT3 phosphorylation and HNSCC cell lines and xenograft models.
- Identified the specific cysteine residue targeted by GSNO-mediated S-nitrosylation.
Main Results:
- STAT3 undergoes S-nitrosylation and S-glutathionylation in stimulated microglia.
- GSNO inhibits STAT3 phosphorylation at Tyr705 via S-nitrosylation of STAT3 at Cys259, not JAK2.
- GSNO treatment reduced HNSCC cell proliferation, increased apoptosis, and inhibited tumor growth in xenograft models, with enhanced efficacy when combined with radiation and cisplatin.
Conclusions:
- STAT3 S-nitrosylation at Cys259 is a key mechanism for inhibiting JAK2/STAT3 pathway activation.
- GSNO demonstrates therapeutic potential for treating HNSCC by inhibiting STAT3 signaling.
- Targeting STAT3 with GSNO offers a promising strategy for diseases involving inflammation and abnormal cell proliferation, including cancer.
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