TXNIP mediates the differential responses of A549 cells to sodium butyrate and sodium 4-phenylbutyrate treatment.
TXNIP mediates the differential responses of A549 cells to sodium butyrate and sodium 4-phenylbutyrate treatment.
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TXNIP 介导 A549 细胞对丁酸钠和 4-苯基丁酸钠处理的差异反应。
DOI：
10.1002/cam4.977
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发表时间：
2017-02
期刊：
影响因子：
4
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Jin X;Wu N;Dai J;Li Q;Xiao X
丁酸钠(NaBu)和4-苯基丁酸钠(4PBA)在癌症治疗中具有广阔的前景，但其潜在的分子机制尚不清楚。在这里，我们展示了NaBu和4PBA诱导的A549细胞死亡是不同的。NaBu诱导的A549细胞死亡水平明显高于4PBA。基因表达微阵列发现，在NaBu处理的A549细胞中，有5000多个转录本发生了改变(>；1.5倍)，但在4PBA中改变的转录本不到2000个。此外，100多个细胞周期相关基因被NaBu强烈抑制，但被4PBA轻微抑制；只有在4PBA处理的细胞中，只有少数基因显著上调。通过其他实验进一步验证了基因的表达。此外，用这些药物处理的A549细胞表现出葡萄糖消耗、caspase3/7激活和组蛋白修饰的变化，以及增强线粒体超氧化物的产生。NaBu(30~40倍的信使核糖核酸)对A549细胞有较强的TXNIP诱导作用，而4-PBA(2~5倍)对TXNIP的诱导作用较弱。在A549细胞中，通过shRNA敲除TXNIP可显著抑制caspase3/7的激活并恢复细胞活力，而TXNIP过表达仅在NaBu处理的细胞中显著增加caspase3/7的激活和细胞死亡。此外，TXNIP还可调节NaBu诱导的H4K5乙酰化和H3K4三甲基化，这可能是通过增加WDR5的表达实现的。最后，我们证明了4PBA诱导了线粒体超氧化物相关的细胞死亡，而NaBu主要通过TXNIP介导的途径实现这一过程。以上数据可能对今后的临床应用有所裨益。
Sodium butyrate (NaBu) and sodium 4‐phenylbutyrate (4PBA) have promising futures in cancer treatment; however, their underlying molecular mechanisms are not clearly understood. Here, we show A549 cell death induced by NaBu and 4PBA are not the same. NaBu treatment induces a significantly higher level of A549 cell death than 4PBA. A gene expression microarray identified more than 5000 transcripts that were altered (>1.5‐fold) in NaBu‐treated A549 cells, but fewer than 2000 transcripts that were altered in 4PBA. Moreover, more than 100 cell cycle‐associated genes were greatly repressed by NaBu, but slightly repressed by 4PBA; few genes were significantly upregulated only in 4PBA‐treated cells. Gene expression was further validated by other experiments. Additionally, A549 cells that were treated with these showed changes in glucose consumption, caspase 3/7 activation and histone modifications, as well as enhanced mitochondrial superoxide production. TXNIP was strongly induced by NaBu (30‐ to 40‐fold mRNA) but was only slightly induced by 4PBA (two to fivefold) in A549 cells. TXNIP knockdown by shRNA in A549 cells significantly attenuated caspase 3/7 activation and restored cell viability, while TXNIP overexpression significantly increased caspase 3/7 activation and cell death only in NaBu‐treated cells. Moreover, TXNIP also regulated NaBu‐ but not 4PBA‐induced H4K5 acetylation and H3K4 trimethylation, possibly by increasing WDR5 expression. Finally, we demonstrated that 4PBA induced a mitochondrial superoxide‐associated cell death, while NaBu did so mainly through a TXNIP‐mediated pathway. The above data might benefit the future clinic application.