Trichostatin A induces p53-dependent endoplasmic reticulum stress in human colon cancer cells
Trichostatin A induces p53-dependent endoplasmic reticulum stress in human colon cancer cells
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曲古抑菌素 A 在人结肠癌细胞中诱导 p53 依赖性内质网应激
DOI：
10.3892/ol.2018.9641
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发表时间：
2019-01-01
期刊：
影响因子：
2.9
通讯作者：
Zhang, Bo
中科院分区：
文献类型：
--
作者：
Dai, Limeng;He, Gang;Zhang, Bo
曲古抑菌素A（TSA）具有多种抗癌作用，可影响癌细胞的细胞周期阻滞、细胞增殖和凋亡。TSA和内质网（ER）功能之间的潜在关联已被提出，但其涉及ER应激诱导的抗癌机制尚不清楚。p53先前已被证明调节ER功能以响应应激，但其涉及TSA和ER应激在癌细胞中的作用知之甚少。目前的研究确定TSA在野生型（WT）HCT 116人结肠癌细胞中诱导ER应激。TSA处理后，ER应激标志物GRP 78和GRP 94显著增加，而其启动子区域没有过度乙酰化。肌醇需要酶1（IRE 1）/X-box结合蛋白1（XBP 1）途径是由于磷酸化的IRE 1和剪接的XBP 1与ER应激相关。然而，荧光素酶报告基因分析表明，剪接事件在HCT 116 TP 53（-/-）细胞中减弱。此外，细胞活力和凋亡被揭示依赖于p53在TSA处理。与WT HCT 116细胞相比，经TSA处理的HCT 116 TP 53（-/-）细胞的细胞活力增加，凋亡率降低。总之，目前的研究表明，TSA可能通过p53依赖的机制诱导结肠癌细胞的ER应激。这提供了可能有助于开发利用TSA抗癌功能的治疗的信息。
Trichostatin A (TSA) has been demonstrated to exhibit various anticancer effects that influence cell cycle arrest, cell proliferation and apoptosis of cancer cells. A potential association between TSA and endoplasmic reticulum (ER) function has been suggested but its anticancer mechanism involving the induction of ER stress is unknown. p53 has previously been demonstrated to regulate ER function in response to stress but its role involving TSA and ER stress in cancer cells is poorly understood. The current study identified that TSA induced ER stress in wild type (WT) HCT116 human colon cancer cells. Following TSA treatment, the ER stress markers GRP78 and GRP94 significantly increased without hyperacetylation of their promoter regions. The inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) pathway was implicated due to an association of phosphorylated IRE1 and spliced XBP1 with ER stress. However, luciferase reporter assay indicated that splicing events were attenuated in HCT116 TP53(-/-) cells. Furthermore, cell viability and apoptosis were revealed to depend on p53 during TSA treatment. Cell viability increased and the apoptosis rate decreased in HCT116 TP53(-/-) cells compared with WT HCT116 cells undergoing TSA treatment. In conclusion, the current study revealed that TSA may induce ER stress via a p53-dependent mechanism in colon cancer cells. This provides information that may assist the development of treatments that exploit the anticancer function of TSA.