具有PI3K激活的瘤对饮食限制有抗性
Nada Y Kalaany1, David M Sabatini
1Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature
|March 13, 2009
概括
饮食限制会影响瘤生长,但耐药性与酸-3-酶 (PI3K) 途径有关. 激活PI3K中的突变使瘤抵抗饮食限制,这表明有针对性的治疗方法.
科学领域:
- 在瘤学瘤学.
- 代谢途径 代谢途径
- 癌症生物学 癌症生物学
背景情况:
- 已知饮食限制 (DR) 可以延迟瘤发生率并减缓瘤生长.
- 对瘤敏感性或对DR的耐药性的潜在机制尚未完全理解.
研究的目的:
- 研究确定癌细胞对饮食限制敏感性的分子机制.
- 为了确定特定的途径,赋予对DR的抗增长效应的耐药性.
主要方法:
- 利用人类癌症细胞系在小鼠中作为瘤异种移植生长.
- 在具有不同PI3K通路激活的细胞系中比较瘤生长和对DR的敏感性.
- 基因改造的癌细胞改变PI3K通路活性 (例如,用野生类型替换突变PI3K,恢复PTEN表达).
- 在前列腺癌的PTEN-null小鼠模型和缺乏构成PI3K信号的肺癌模型中评估了DR效应.
主要成果:
- 具有构成性激活酸-3-酶 (PI3K) 途径的癌细胞系对DR的抗生长效应表现出抵抗力.
- 这些耐药细胞可以独立于胰岛素或类似胰岛素的生长因子1繁殖.
- 恢复野生型PI3K或PTEN表达转换了耐药瘤到DR敏感的表型.
- DR没有影响PTEN-null前列腺癌的生长,但在PI3K独立的肺癌模型中降低了瘤负担.
结论:
- PI3K通路是瘤对饮食限制敏感性的关键决定因素.
- 在PI3K路径中激活突变会对DR产生抗性.
- 这些发现表明,PI3K通路激活状态可以预测癌症对DR模拟疗法的反应.
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