title: S-Nitrosoglutathione-mediated STAT3 regulation in efficacy of radiotherapy and cisplatin therapy in head and neck squamous cell carcinoma.
abstract: S-nitrosoglutathione (GSNO) is an endogenous nitric oxide (NO) carrier that plays a critical role in redox based NO signaling. Recent studies have reported that GSNO regulates the activities of STAT3 and NF-κB via S-nitrosylation dependent mechanisms. Since STAT3 and NF-κB are key transcription factors involved in tumor progression, chemoresistance, and metastasis of head and neck cancer, we investigated the effect of GSNO in cell culture and mouse xenograft models of head and neck squamous cell carcinoma (HNSCC). For the cell culture studies, three HNSCC cell lines were tested (SCC1, SCC14a and SCC22a). All three cell lines had constitutively activated (phosphorylated) STAT3 (Tyr(705)). GSNO treatment of these cell lines reversibly decreased the STAT3 phosphorylation in a concentration dependent manner. GSNO treatment also decreased the basal and cytokine-stimulated activation of NF-κB in SCC14a cells and reduced the basal low degree of nitrotyrosine by inhibition of inducible NO synthase (iNOS) expression. The reduced STAT3/NF-κB activity by GSNO treatment was correlated with the decreased cell proliferation and increased apoptosis of HNSCC cells. In HNSCC mouse xenograft model, the tumor growth was reduced by systemic treatment with GSNO and was further reduced when the treatment was combined with radiation and cisplatin. Accordingly, GSNO treatment also resulted in decreased levels of phosphorylated STAT3. In summary, these studies demonstrate that GSNO treatment blocks the NF-κB and STAT3 pathways which are responsible for cell survival, proliferation and that GSNO mediated mechanisms complement cispaltin and radiation therapy, and thus could potentiate the therapeutic effect in HNSCC.
authors.affiliation: Departments of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Kolanjiappan
authors.initials: K
authors.lastname: Kaliyaperumal
authors.affiliation: Departments of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Anand K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Departments of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: McDonald
authors.affiliation: Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Jasdeep S
authors.initials: JS
authors.lastname: Dhindsa
authors.affiliation: Departments of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Yount
authors.affiliation: Pathology and Laboratory Medicine Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC 29401, USA.
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: wonj@musc.edu.
authors.forename: Je-Seong
authors.initials: JS
authors.lastname: Won
authors.affiliation: Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: singhi@musc.edu.
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005720:Gamma Rays / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010766:Phosphorylation; D026422:S-Nitrosoglutathione / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D026422:S-Nitrosoglutathione; D002945:Cisplatin
keywords: Cisplatin; Head and neck cancer; NF-κB; Radiotherapy; S-Nitrosoglutathione; STAT3