The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation
The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation
复制标题
DOI：
10.1016/j.cell.2004.12.040
复制
发表时间：
2005-03-25
期刊：
影响因子：
64.5
通讯作者：
Thomas, G
中科院分区：
文献类型：
--
作者：
Beuvink, I;Boulay, A;Thomas, G
尽管DNA损伤剂已经彻底改变了针对实体瘤的化疗，但狭窄的治疗窗口加上严重的副作用限制了它们的广泛应用。在这里，我们表明，RAD001（依维莫司），雷帕霉素衍生物，显着增强顺铂诱导的野生型p53细胞凋亡，但不是突变型p53肿瘤细胞。使用表达野生型mTOR cDNA或不结合RAD001的突变体的等基因肿瘤细胞系证明RAD001的作用是通过抑制mTOR功能。我们进一步表明，RAD001通过抑制p53诱导的p21表达，使细胞对顺铂敏感。出乎意料的是，这种效果归因于对p2l翻译的小但显著的抑制及其短半衰期。这些发现提供了将DNA损伤剂与RAD 001结合的分子理论基础，表明对主要合成代谢过程的一般作用可能会显着提高已建立的药物方案在治疗实体瘤癌症患者中的疗效。
Although DNA damaging agents have revolutionized chemotherapy against solid tumors, a narrow therapeutic window combined with severe side effects has limited their broader use. Here we show that RAD001 (everolimus), a rapamycin derivative, dramatically enhances cisplatin-induced apoptosis in wild-type p53, but not mutant p53 tumor cells. The use of isogenic tumor cell lines expressing either wild-type mTOR cDNA or a mutant that does not bind RAD001 demonstrates that the effects of RAD001 are through inhibition of mTOR function. We further show that RAD001 sensitizes cells to cisplatin by inhibiting p53-induced p21 expression. Unexpectedly, this effect is attributed to a small but significant inhibition of p2l translation combined with its short half-life. These findings provide the molecular rationale for combining DNA damaging agents with RAD001, showing that a general effect on a major anabolic process may dramatically enhance the efficacy of an established drug protocol in the treatment of cancer patients with solid tumors.