Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL
Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL
复制标题
DOI：
10.1182/blood-2010-03-275628
复制
发表时间：
2010-10-14
期刊：
影响因子：
20.3
通讯作者：
Marconi, Pierfrancesco
中科院分区：
文献类型：
--
作者：
Rosati, Emanuela;Sabatini, Rita;Marconi, Pierfrancesco
更好地了解 B 慢性淋巴细胞白血病 (B-CLL) 细胞的凋亡信号传导可能有助于确定新的治疗策略。本研究调查了 B-CLL 细胞自发凋亡中的内质网 (ER) 应激信号传导，以及操纵 ER 应激是否会增加其凋亡。结果表明，由 caspase-4 启动并涉及 caspase-8 和 -3 的新型 ER 应激触发 caspase 级联在自发 B-CLL 细胞凋亡中发挥重要作用。 B-CLL 细胞中 ER 应激诱导的细胞凋亡还涉及 CHOP/GADD153 上调、JNK1/2 磷酸化增加以及 caspase-8 介导的 Bap31 到 Bap20 的裂解，已知将细胞凋亡信号从 ER 传播到线粒体。在离体 B-CLL 细胞中，也会发生一些与线粒体途径相关的凋亡事件，包括线粒体细胞色素 c 释放和 caspase-9 加工。然而，药理抑制研究表明 caspase-9 在 B-CLL 细胞凋亡中发挥次要作用。 ER 应激还通过增加 BiP/GRP78 表达来触发 B-CLL 细胞的生存信号。通过 siRNA 下调 BiP/GRP78 来操纵 ER 信号传导，或用 2 种众所周知的 ER 应激诱导剂（衣霉素和毒胡萝卜素）处理 B-CLL 细胞，可增加其凋亡。总体而言，我们的研究结果表明 ER 触发 B-CLL 细胞凋亡的重要途径，并表明对 ER 信号传导的遗传和药理学操作可能代表一种重要的治疗策略。 （血。2010；116（15）：2713-2723）
A better understanding of apoptotic signaling in B-chronic lymphocytic leukemia (B-CLL) cells may help to define new therapeutic strategies. This study investigated endoplasmic reticulum (ER) stress signaling in spontaneous apoptosis of B-CLL cells and whether manipulating ER stress increases their apoptosis. Results show that a novel ER stress-triggered caspase cascade, initiated by caspase-4 and involving caspase-8 and -3, plays an important role in spontaneous B-CLL cell apoptosis. ER stress-induced apoptosis in B-CLL cells also involves CHOP/GADD153 up-regulation, increased JNK1/2 phosphorylation, and caspase-8-mediated cleavage of Bap31 to Bap20, known to propagate apoptotic signals from ER to mitochondria. In ex vivo B-CLL cells, some apoptotic events associated with mitochondrial pathway also occur, including mitochondrial cytochrome c release and caspase-9 processing. However, pharmacologic inhibition studies show that caspase-9 plays a minor role in B-CLL cell apoptosis. ER stress also triggers survival signals in B-CLL cells by increasing BiP/GRP78 expression. Manipulating ER signaling by siRNA down-regulation of BiP/GRP78 or treating B-CLL cells with 2 well-known ER stress-inducers, tunicamycin and thapsigargin, increases their apoptosis. Overall, our findings show that ER triggers an essential pathway for B-CLL cell apoptosis and suggest that genetic and pharmacologic manipulation of ER signaling could represent an important therapeutic strategy. (Blood. 2010;116(15):2713-2723)