在癌症治疗中,合成致命的代谢向细胞衰老
Jan R Dörr1, Yong Yu, Maja Milanovic
1Charité-Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353 Berlin, Germany.
Nature
|August 16, 2013
概括
治疗诱导的衰老 (TIS) 涉及代谢重编程,增加葡萄糖的使用和ATP的产生. 针对这些代谢需求,可以选择性地消除衰老的瘤细胞,改善治疗结果.
科学领域:
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
- 代谢过程中的代谢.
背景情况:
- 活性化瘤基因和化疗诱导细胞衰老,一种终端生长停止的状态.
- 治疗诱导的衰老 (TIS) 改善了结果,但衰老的瘤细胞需要消除.
- 衰老涉及像H3K9me3这样的基因组修饰,并且与衰老相关的分泌表型 (SASP) 有关.
研究的目的:
- 阐明 TIS 中代谢重编程的机制.
- 探索对TIS中的代谢漏洞的治疗利用.
- 调查Suv39h1在TIS依赖的代谢变化中的作用.
主要方法:
- 使用了Eμ-myc转基因小鼠淋巴瘤模型.
- 对TIS有能力和TIS无能力 (Suv39h1(-)) 淋巴瘤进行比较.
- 分析了葡萄糖利用率,ATP生产,蛋白质毒性压力,内质网膜压力,未折叠的蛋白质反应 (UPR) 和无处不在.
- 评估对葡萄糖利用和自抑制的敏感性.
- 研究了卡斯帕斯-12和卡斯帕斯-3介导的亡.
- 在体内使用药理学向.
主要成果:
- 与TIS无能淋巴瘤相比,TIS有能力的淋巴瘤显示葡萄糖利用率和ATP产量增加.
- 这种代谢转变与蛋白质毒性压力,SASP,内分泌网膜压力,UPR和增加的无处不在性有关.
- 通过阻断葡萄糖利用或自,诱导亡来选择性地消除TIS淋巴瘤.
- 对这些代谢需求的药理向导致瘤回归和改善结果.
结论:
- TIS表现出由蛋白质毒性压力和SASP驱动的超级catabolic性质.
- 在TIS中的代谢漏洞,特别是葡萄糖利用和自,是可以在治疗上利用的.
- 合成致死性代谢向是改善癌症治疗结果的有希望的策略.
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