与HSP70的PER2相互作用通过降低AKT稳定性,促进口腔状癌细胞中的cuproptosis
Wenguang Yu1, Shilin Yin1, Hong Tang1
1Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Cell death & disease
|March 21, 2025
概括
生物钟基因Period2 (PER2) 调节了口腔状细胞癌 (OSCC) 中一种新的细胞死亡途径cuproptosis. 激活PER2和激活转录因子3 (ATF3) 显示出通过诱导cuproptosis治疗OSCC的希望.
科学领域:
- 细胞生物学 细胞生物学
- 分子瘤学分子瘤学
- 癌症新陈代谢 癌症新陈代谢
背景情况:
- 口腔状细胞癌 (OSCC) 由于预后不佳和机制不太清楚,提出了重大的临床挑战.
- 型亡是一种影响线粒体新陈代谢的新型调节性细胞死亡形式,为OSCC的治疗干预提供了潜在的新途径.
研究的目的:
- 研究生物钟基因Period2 (PER2) 在OSCC中调节cuproptosis中的作用.
- 阐明PER2影响OSCC中cuproptosis和AKT信号的分子机制.
- 探索针对ATF3-PER2轴在OSCC治疗中的治疗潜力.
主要方法:
- 在OSCC组织和细胞系中对PER2表达的定量分析.
- 在体外和体内实验中,涉及PER2过度表达和淘汰的实验.
- 研究PER2,HSP70和AKT之间的蛋白质-蛋白质相互作用.
- 评估亡标志物 (DLAT,PDHB,SLC31A1) 和AKT通路活性.
- 在OSCC异种移植模型中评估ATF3诱导,PER2上调和铜离子孔治疗的联合抗瘤疗效.
主要成果:
- 发现PER2在OSCC中表达不充分,与受抑制的cuproptosis相关.
- 在OSCC细胞中,PER2的过度表达促进了cuproptosis,通过抑制AKT通路和上调关键的cuproptosis相关基因 (DLAT,PDHB,SLC31A1).
- PER2的机制包括与HSP70结合,破坏HSP70-AKT相互作用,并促进AKT降解.
- 激活转录因子3 (ATF3) 作为上游调节剂,通过转录激活PER2并促进cuproptosis.
- 针对ATF3和PER2的联合治疗与elesclomol在体内表现出增强的抗瘤作用.
结论:
- 在OSCC中,ATF3-PER2轴在调节cuproptosis中起着至关重要的作用.
- 针对PER2的有针对性的上调,可能由ATF3介导,是OSCC的新治疗策略.
- 通过PER2和ATF3激活诱导cuproptosis的组合疗法可以显著改善OSCC患者的预后.
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