S-Nitrosoglutathione-mediated STAT3 regulation in efficacy of radiotherapy and cisplatin therapy in head and neck squamous cell carcinoma.
S-Nitrosoglutathione-mediated STAT3 regulation in efficacy of radiotherapy and cisplatin therapy in head and neck squamous cell carcinoma.
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DOI：
10.1016/j.redox.2015.07.001
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发表时间：
2015-12
期刊：
影响因子：
11.4
通讯作者：
Singh I
中科院分区：
文献类型：
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作者：
Kaliyaperumal K;Sharma AK;McDonald DG;Dhindsa JS;Yount C;Singh AK;Won JS;Singh I
S-亚硝基谷胱甘肽 (GSNO) 是一种内源性一氧化氮 (NO) 载体，在基于氧化还原的 NO 信号传导中发挥着关键作用。最近的研究表明，GSNO 通过 S-亚硝基化依赖机制调节 STAT3 和 NF-κB 的活性。由于 STAT3 和 NF-κB 是参与头颈癌肿瘤进展、化疗耐药和转移的关键转录因子，我们研究了 GSNO 在头颈鳞状细胞癌 (HNSCC) 细胞培养和小鼠异种移植模型中的作用。对于细胞培养研究，测试了三种 HNSCC 细胞系（SCC1、SCC14a 和 SCC22a）。所有三种细胞系均已组成型激活（磷酸化）STAT3 (Tyr705)。这些细胞系的 GSNO 处理以浓度依赖性方式可逆地降低了 STAT3 磷酸化。 GSNO 治疗还降低了 SCC14a 细胞中 NF-κB 的基础和细胞因子刺激的激活，并通过抑制诱导型 NO 合酶 (iNOS) 表达降低了基础低程度的硝基酪氨酸。 GSNO 处理降低的 STAT3/NF-κB 活性与 HNSCC 细胞增殖减少和凋亡增加相关。在 HNSCC 小鼠异种移植模型中，GSNO 全身治疗可减少肿瘤生长，并在联合放疗和顺铂治疗时进一步减少肿瘤生长。因此，GSNO 处理也导致磷酸化 STAT3 水平降低。总之，这些研究表明，GSNO 治疗阻断了负责细胞存活、增殖的 NF-κB 和 STAT3 通路，并且 GSNO 介导的机制补充了顺铂和放射治疗，因此可以增强 HNSCC 的治疗效果。 S-亚硝基谷胱甘肽 (GSNO) 抑制 HNSCC 细胞中 STAT3 和 NF-κB 的激活。 GSNO 诱导 HNSCC 细胞的细胞周期停滞和凋亡。 GSNO 减少 HNSCC 细胞中 iNOS 和 VEGF 的产生。 GSNO 增强 HNSCC 小鼠异种移植模型中放化疗的疗效。
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 (Tyr705). 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. S-nitrosoglutathione (GSNO) inhibits activations of STAT3 and NF-κB in HNSCC cells. GSNO induces cell cycle arrest and apoptosis of HNSCC cells. GSNO decreases iNOS and VEGF production in HNSCC cells. GSNO enhances efficacy of chemoradiation therapy in HNSCC mouse xenograft model.