Human rpL3 plays a crucial role in cell response to nucleolar stress induced by 5-FU and L-OHP.
Human rpL3 plays a crucial role in cell response to nucleolar stress induced by 5-FU and L-OHP.
复制标题
DOI：
10.18632/oncotarget.2591
复制
发表时间：
2014-11-30
期刊：
影响因子：
--
通讯作者：
Russo G
中科院分区：
文献类型：
--
作者：
Esposito D;Crescenzi E;Sagar V;Loreni F;Russo A;Russo G
最近的证据表明，包括5-FU和L-OHP在内的多种DNA损伤剂损害核糖体生物合成，激活核糖体应激途径。在这里，我们证明，在肺和结肠癌细胞系缺乏p53，5-FU和L-OHP化疗的疗效取决于rpL 3的状态。具体而言，我们证明了5-FU和L-OHP诱导的核糖体应激与rpL 3的上调及其作为核糖体游离形式的积累有关。我们表明，rpL 3参与细胞对化疗的反应，作为细胞周期，凋亡和DNA修复的关键调节因子，通过调节p21的表达。此外，我们证明rpL 3能够控制DNA修复也独立于细胞的p21状态。值得注意的是，rpL 3的沉默消除了5-FU和L-OH的细胞毒性作用，表明rpL 3的缺失使化疗药物无效。综合以上研究结果，有助于阐明5-FU和L-OHP的作用机制，并为临床更有效地使用这些药物治疗癌症做出贡献。
Recent evidence showed that a variety of DNA damaging agents including 5-FU and L-OHP impairs ribosomal biogenesis activating a ribosomal stress pathway. Here, we demonstrate that in lung and colon cancer cell lines devoid of p53, the efficacy of 5-FU and L-OHP chemotherapy depends on rpL3 status. Specifically, we demonstrate that ribosomal stress induced by 5-FU and L-OHP is associated to up-regulation of rpL3 and its accumulation as ribosome-free form. We show that rpL3 participates in the cell response to chemotherapy acting as a critical regulator of cell cycle, apoptosis and DNA repair, by modulating p21 expression. Moreover, we demonstrate that rpL3 is able to control DNA repair also independently from p21 status of cell. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of 5-FU and L-OH indicating that the loss of rpL3 makes chemotherapy drugs ineffective. Taking together our results shed light on 5-FU and L-OHP mechanism of action and contribute to more effective clinical use of these drugs in cancer therapy.
登录
查看更多内容
影响因子：
14.9
作者：
Grimm T;Hölzel M;Rohrmoser M;Harasim T;Malamoussi A;Gruber-Eber A;Kremmer E;Eick D
通讯作者：
Eick D
影响因子：
7.8
作者：
Kim, Jong-Soo;Krasieva, Tatiana B;Kurumizaka, Hitoshi;Chen, David J;Taylor, A Malcolm R;Yokomori, Kyoko
通讯作者：
Yokomori, Kyoko
影响因子：
5.3
作者：
Dai, MS;Zeng, SX;Lu, H
通讯作者：
Lu, H
影响因子：
8
作者：
Iadevaia, V.;Caldarola, S.;Loreni, F.
通讯作者：
Loreni, F.
影响因子：
4.7
作者：
Castro, Maria E.;Leal, Juan F. M.;Carnero, Amancio
通讯作者：
Carnero, Amancio