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首页> 外文期刊>Cellular Physiology and Biochemistry >Integrated High Throughput Analysis Identifies GSK3 as a Crucial Determinant of p53-Mediated Apoptosis in Lung Cancer Cells
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Integrated High Throughput Analysis Identifies GSK3 as a Crucial Determinant of p53-Mediated Apoptosis in Lung Cancer Cells

机译：集成的高通量分析确定GSK3是p53介导的肺癌细胞凋亡的关键决定因素。

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>Background/Aims: p53 dysfunction is frequently observed in lung cancer. Although restoring the tumour suppressor function of p53 is recently approved as a putative strategy for combating cancers, the lack of understanding of the molecular mechanism underlying p53-mediated lung cancer suppression has limited the application of p53-based therapies in lung cancer. Methods and Results: Using RNA sequencing, we determined the transcriptional profile of human non-small cell lung carcinoma A549 cells after treatment with two p53-activating chemical compounds, nutlin and RITA, which could induce A549 cell cycle arrest and apoptosis, respectively. Bioinformatics analysis of genome-wide gene expression data showed that distinct transcription profiles were induced by nutlin and RITA and 66 pathways were differentially regulated by these two compounds. However, only two of these pathways, 'Adherens junction' and 'Axon guidance', were found to be synthetic lethal with p53 re-activation, as determined via integrated analysis of genome-wide gene expression profile and short hairpin RNA (shRNA) screening. Further functional protein association analysis of significantly regulated genes associated with these two synthetic lethal pathways indicated that GSK3 played a key role in p53-mediated A549 cell apoptosis, and then gene function study was performed, which revealed that GSK3 inhibition promoted p53-mediated A549 cell apoptosis in a p53 post-translational activity-dependent manner. Conclusion: Our findings provide us with new insights regarding the mechanism by which p53 mediates A549 apoptosis and may cast light on the development of more efficient p53-based strategies for treating lung cancer.
机译：> 背景/目的： 在肺癌中经常观察到p53功能异常。尽管最近已批准恢复p53的肿瘤抑制功能作为抗击癌症的策略，但由于对p53介导的肺癌抑制的分子机制缺乏了解，限制了基于p53的疗法在肺癌中的应用。 方法和结果： 我们使用RNA测序确定了两种非p53激活化合物Nutlin和RITA处理后人非小细胞肺癌A549细胞的转录谱分别可以诱导A549细胞周期停滞和凋亡。对全基因组基因表达数据的生物信息学分析表明，nutlin和RITA诱导了不同的转录谱，并且这两种化合物差异调节了66种途径。然而，通过对全基因组基因表达谱和短发夹RNA（shRNA）筛选的综合分析确定，只有这些途径中的两个途径“ Adherens交界处”和“ Axon引导”是合成致死性的p53再次激活。 。对这两个合成致死途径相关的显着调节基因的进一步功能蛋白关联分析表明，GSK3在p53介导的A549细胞凋亡中起着关键作用，然后进行了基因功能研究，这表明GSK3抑制作用促进了p53介导的A549细胞的凋亡。凋亡以翻译后活性依赖的方式表达。 结论： 我们的发现为我们提供了有关p53介导A549细胞凋亡的机制的新见解，并可能为基于p53的更有效的肺癌治疗策略的发展提供参考。 。

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