在非小细胞肺癌中USP18通过稳定SHANK1表达方式通过除菌化来赋予帕克利塔塞尔耐药性
Lixun Chai1, Yanlong Sun1, Yunfei Wang1
1Department of Thoracic surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi, China.
Journal of biochemical and molecular toxicology
|March 17, 2025
概括
乌比基特异性蛋白酶18 (USP18) 通过稳定SHANK1.1,促进非小细胞肺癌 (NSCLC) 中的帕克利塔塞尔耐药性. USP18二基化SHANK1,增强其表达并赋予其抗性. 沉默USP18恢复了NSCLC中对帕克利塔塞尔的敏感性.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 非小细胞肺癌 (NSCLC) 是癌症死亡的主要原因.
- 帕克利塔塞尔 (PTX) 是NSCLC的关键化疗剂,但耐药性仍然是一个重大挑战.
- 乌比基特异性蛋白酶18 (USP18) 与癌症进展有关,但其在PTX耐药性中的作用尚不清楚.
研究的目的:
- 研究USP18在NSCLC中帕克利塔克塞尔耐药性的作用和机制.
- 阐明USP18,SHANK1和PTX在NSCLC细胞中的敏感性之间的关系.
主要方法:
- 定量实时PCR (qRT-PCR) 和西布洛特用于评估USP18和SHANK1的表达.
- 细胞增殖,细胞亡和IC50测定 (殖民地形成,流细胞计,CCK-8) 以确定PTX耐药性.
- 糖溶解试验 (葡萄糖消耗,乳酸生产,ATP水平) 和共免疫沉 (Co-IP) 以验证蛋白质相互作用和二氧化.
- 在体内进行动物实验以进一步验证.
主要成果:
- 在抗PTX的NSCLC组织和细胞中,USP18显著上调.
- USP18沉默抑制了增殖和糖解,诱导了亡,并在耐性NSCLC细胞中增强了PTX敏感性.
- USP18对SHANK1进行双化和稳定,而SHANK1在抗PTX细胞中也具有很高的表达.
- SHANK1缺乏增加了PTX敏感性,而SHANK1过度表达逆转了USP18沉默的影响.
- 通过调节SHANK1.1,USP18静音增强了PTX诱导的生长抑制.
结论:
- USP18通过duebiquitination稳定SHANK1的表达,从而使NSCLC具有抗帕克利塔塞尔的作用.
- USP18和SHANK1代表了克服NSCLC中PTX耐药性的潜在治疗点.
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