S-nitrosylation of the Peroxiredoxin-2 promotes S-nitrosoglutathione-mediated lung cancer cells apoptosis via AMPK-SIRT1 pathway
S-nitrosylation of the Peroxiredoxin-2 promotes S-nitrosoglutathione-mediated lung cancer cells apoptosis via AMPK-SIRT1 pathway
复制标题
Peroxiredoxin-2 的 S-亚硝基化通过 AMPK-SIRT1 途径促进 S-亚硝基谷胱甘肽介导的肺癌细胞凋亡
DOI：
10.1038/s41419-019-1561-x
复制
发表时间：
2019-04-15
影响因子：
9
通讯作者：
Gu, Yuchao
中科院分区：
文献类型：
--
作者：
Zhang, Yihan;Sun, Changning;Gu, Yuchao
蛋白质S-亚硝基化是通过连接一氧化氮（NO）基团对半胱氨酸巯基进行的基于氧化还原的翻译后修饰，负责多种信号传导效应。S-亚硝基化的失调可能与癌症细胞凋亡抗性和癌症治疗结果直接相关，强调了S-亚硝基化在癌症中的重要性。过氧化物氧还蛋白-2（Peroxiredoxin-2，Prdx 2）是一种抗氧化酶，在保护癌细胞免受过氧化氢（H2 O2）引起的氧化自由基损伤中发挥重要作用，是肿瘤治疗的潜在靶点。我们的研究表明，S-亚硝基谷胱甘肽（GSNO）作为内源性NO载体，通过亚硝基化Prdx 2诱导肺癌细胞凋亡。Prdx 2在Cys 51和Cys 172位点的亚硝基化破坏了Prdx 2二聚体的形成，抑制了Prdx 2的抗氧化活性，导致内源性H2 O2的积累。H2 O2激活AMPK，然后使SIRT 1磷酸化并抑制其对A549细胞中的p53或NCI-H1299细胞中的FOXO 1的脱乙酰化活性。综上所述，我们的研究结果阐明了在肺癌细胞凋亡中Cys 51和Cys 172位点的Prdx 2 S-亚硝基化的作用和机制，这一发现为管理肺癌中异常的Prdx 2活性提供了有效的肺癌治疗策略。
Protein S-nitrosylation, the redox-based posttranslational modification of a cysteine thiol by the attachment of a nitric oxide (NO) group, is responsible for a variety of signaling effects. Dysregulation of S-nitrosylation may be directly linked to cancer apoptotic resistance and cancer therapy outcomes, emphasizing the importance of S-nitrosylation in cancer. Peroxiredoxin-2 (Prdx2), an antioxidant enzyme, plays an important role in the protection of cancer cells from oxidative radical damage caused by hydrogen dioxide (H2O2), which is a potential target for cancer therapy. Our studies showed that, as an endogenous NO carrier, S-nitrosoglutathione (GSNO) induced apoptosis in lung cancer cells via nitrosylating Prdx2. The nitrosylation of Prdx2 at Cys51 and Cys172 sites disrupted the formation of Prdx2 dimer and repressed the Prdx2 antioxidant activity, causing the accumulation of endogenous H2O2. H2O2 activated AMPK, which then phosphorylated SIRT1 and inhibited its deacetylation activity toward p53 in A549 cells or FOXO1 in NCI-H1299 cells. Taken together, our results elucidate the roles and mechanisms of Prdx2 S-nitrosylation at Cys51 and Cys172 sites in lung cancer cells apoptosis and this finding provides an effective lung cancer treatment strategy for managing aberrant Prdx2 activity in lung cancers.