mTORC1-介导的翻译延长限制了肠道瘤的发病和生长
William J Faller1, Thomas J Jackson2, John Rp Knight2
1Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Nature
|November 11, 2014
概括
在结直肠癌细胞中APC功能的丧失意外地需要mTORC1驱动的翻译延长,而不是启动. 拉帕米辛治疗通过向这种途径来阻止瘤生长,提供了一种新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 腺多样性大肠杆菌 (APC) 基因失活是结直肠癌 (CRC) 发展的一个关键事件.
- 拉巴胺素 (mTOR) 途径的机械性标调节细胞增殖和瘤生长.
- 目前的理解意味着mTOR在升高调节翻译启动,预测mTOR抑制剂的有限有效性,如在APC缺乏的癌症中拉巴胺.
研究的目的:
- 为了研究mTOR信号传递在缺乏APC的结直肠癌中的作用.
- 为了确定缺少APC功能的癌细胞中的特定漏洞.
- 探索针对结直肠癌mTOR途径的治疗干预措施.
主要方法:
- 使用了Apc缺陷结直肠瘤的小鼠模型.
- 分析了蛋白质合成,专注于翻译启动和延长.
- 研究了mTOR复合体1 (mTORC1) 在肠细胞增殖中的信号传递机制.
- 评估了拉巴胺治疗对已确定的APC缺陷腺瘤的影响.
主要成果:
- mTORC1活动对于缺乏Apc的肠细胞的增殖至关重要,但不是野生类型.
- 缺乏APC的细胞表现出蛋白质合成的增加,翻译延长是速度限制的步骤.
- 通过mTORC1介导的真核延长因子2激酶 (eEF2K) 的抑制对于缺乏APC的细胞增殖至关重要.
- 拉巴胺治疗诱导了已建立的APC缺陷瘤的生长停止和分化.
结论:
- 缺少APC的结直肠癌细胞对mTORC1在翻译延长方面具有独特的依赖性.
- 抑制翻译延长,而不是启动,是一个关键的治疗目标.
- 临床上已批准的药物,如拉巴胺,通过通过mTORC1-S6K轴准eEF2K,显示出治疗缺少APC的大肠直肠瘤的潜力.
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