准ATF6介导的ER应激反应和自阻碍了整合因子驱动的前列腺癌进展
Amanda J Macke1,2, Artem N Pachikov1,2, Taylor E Divita1,2
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
Molecular cancer research : MCR
|June 14, 2023
概括
转移性割抵抗性前列腺癌 (mCRPC) 的进展涉及改变的糖化和戈尔吉失调. 抑制ATF6和自同时降低整合素表达和瘤生长,提供一种潜在的mCRPC疗法.
科学领域:
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
- 生物化学 生物化学
背景情况:
- 前列腺癌进展为致命的转移性抵抗割的前列腺癌 (mCRPC),由αv整合素驱动.
- 这种进展与戈尔吉失调和ATF6分支的激活有关,这是未折叠蛋白质反应 (UPR) 的分支.
- 改变的糖化,特别是N-乙葡萄糖氨基基转移酶-V (MGAT5) 介导的,和Galactin-3 (Gal-3) 聚类与整合素过度表达有关,但潜在的机制尚不清楚.
研究的目的:
- 阐明在前列腺癌进展中将戈尔吉失调,UPR激活和改变的糖化转化联系在一起的机制.
- 研究MGAT5,MGAT3和Gal-3在整合蛋白的局部化和功能中的作用.
- 评估针对ATF6和mCRPC中的自的治疗潜力.
主要方法:
- 在初级和mCRPC样本上进行免疫组织化学 (IHC) 的HALO分析.
- 在前列腺癌细胞系中以乙醇诱导的内质网膜 (ER) 应激模型 (PC-3,DU145).
- 评估戈尔吉形态,蛋白质定位 (MGAT3,Gal-3) 和整体蛋白αv表达.
- 在细胞系和正型瘤模型中抑制ATF6和自 (使用化 - HCQ).
主要成果:
- 在前列腺癌样本中,在血膜 (PM) 上观察到整合素αv和Gal-3之间的强烈关联.
- 戈尔吉分裂和MGAT3错位到ER被确定为MGAT5激活的原因.
- 乙醇暴露加剧了戈尔吉散射,激活了MGAT5和增加了PM整合蛋白表达,将酒精消费与前列腺癌死亡率联系起来.
- ATF6的耗尽减少了戈尔吉碎片和UPR.
- 自抑制 (HCQ) 恢复了戈尔吉结构,挽救了MGAT3局部化,阻止了MGAT5活性,并减少了细胞表面Gal-3.
- 失去Gal-3降低了PM整合素,并增加了它们的内部化.
- 联合ATF6枯竭和HCQ治疗协同减少了整合蛋白αv和Gal-3,抑制了瘤生长,并减少了转移.
结论:
- 戈尔吉分裂和MGAT3错位驱动MGAT5介导的糖化和mCRPC中的整合素过度表达.
- 酒精消费加剧了这些变化,导致前列腺癌死亡率.
- 联合抑制ATF6和自是一种有希望的mCRPC治疗策略,通过减少整合素信号和瘤进展.
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