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Microcystins-LR induced apoptosis via S-nitrosylation of GAPDH in colorectal cancer cells.
Ecotoxicology and Environmental Safety ( IF 6.8 ) Pub Date : 2020-01-02 , DOI: 10.1016/j.ecoenv.2019.110096
Keyi Li 1 , Mengqiu Huang 1 , Pengfei Xu 1 , Meng Wang 1 , Shuangyan Ye 1 , Qianli Wang 1 , Sisi Zeng 1 , Xi Chen 1 , Wenwen Gao 1 , Jianping Chen 1 , Qianbing Zhang 1 , Zhuo Zhong 2 , Yang Sun 3 , Qiuzhen Liu 4
Affiliation  

Microcystins-LR (MC-LR), a cyanobacterial toxins, initiate apoptosis in normal and tumor cells. Nitric oxide produced by iNOS is necessary for MC-LR-induced apoptosis. However, the underlying mechanism of NO mediated MC-LR cytotoxicity remains unclear. Here, we performed in vitro experiments on MC-LR cytotoxicity associated with NO induced S-nitrosyation of GAPDH in human colon cancer cells SW480. MTT assay indicated that MC-LR decreased the cellular viability by high concentration (>1 μM). Flow cytometer assay revealed that apoptosis was core mode for MC-LR cytotoxicity. Griess assay showed that MC-LR exposure increased the release of NO through the function of NOS1 and NOS2 in SW480 cells. In turn, NO stress induced the S-nitrosylated modification of GAPDH leading to its nuclear translocation following Siah1 binding. CHIP assay showed that the nuclear GADPH increased P53 transcript of a panner of apoptosis related genes. Moreover, apoptosis induced by MC-LR could be reduced by GAPDH or si-Siah1 or NOSs inhibitor, L-NAME. Thus, our study verified a molecular mechanism of NO/GAPDH/Siah1 cascade in MC-LR mediated apoptosis in colorectal cancer cells, providing a further understanding the in vitro molecular mechanism of MC-LR colorectal toxicity.

中文翻译:

微囊藻毒素-LR通过大肠癌细胞中GAPDH的S-亚硝基化诱导凋亡。

微囊藻毒素-LR(MC-LR)是一种蓝细菌毒素,可在正常细胞和肿瘤细胞中引发细胞凋亡。iNOS产生的一氧化氮是MC-LR诱导的细胞凋亡所必需的。但是,NO介导的MC-LR细胞毒性的潜在机制仍不清楚。在这里,我们对人结肠癌细胞SW480中NO诱导的GAPDH的S-亚硝基化所引起的MC-LR细胞毒性进行了体外实验。MTT分析表明,MC-LR通过高浓度(> 1μM)降低了细胞活力。流式细胞仪分析表明凋亡是MC-LR细胞毒性的核心模式。Griess分析表明,MC-LR暴露通过SW480细胞中NOS1和NOS2的功能增加了NO的释放。反过来,NO胁迫诱导了GAPDH的S-亚硝基化修饰,导致Siah1结合后其核易位。CHIP分析表明,核GADPH增加了凋亡相关基因的Paner的P53转录。此外,GAPDH或si-Siah1或NOSs抑制剂L-NAME可以减少MC-LR诱导的细胞凋亡。因此,我们的研究验证了NO / GAPDH / Siah1级联在MC-LR介导的结直肠癌细胞凋亡中的分子机制,从而提供了对MC-LR结直肠毒性的体外分子机制的进一步了解。
更新日期:2020-01-02
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