The chemotherapeutic agent bortezomib induces the formation of stress granules.
The chemotherapeutic agent bortezomib induces the formation of stress granules.
复制标题
DOI：
10.1186/1475-2867-10-12
复制
发表时间：
2010-04-29
影响因子：
5.8
通讯作者：
Mazroui R
中科院分区：
文献类型：
--
作者：
Fournier MJ;Gareau C;Mazroui R
细胞质应激颗粒（SG）是非翻译mRNA的专门储存位点，其形成发生在不同的应激条件下，并且通常与细胞存活相关。SG诱导的应激包括辐射、缺氧、病毒感染和特定翻译起始因子的化学抑制剂。FDA批准的药物硼替佐米（Velcade®）是一种26 S蛋白酶体的肽硼酸盐抑制剂，对治疗骨髓瘤和其他血液肿瘤非常有效。实体瘤在很大程度上是硼替佐米难治的。在本研究中，我们研究了硼替佐米治疗后SGs的形成。我们表明硼替佐米有效地诱导癌细胞中SGs的形成。这一过程涉及翻译起始因子eIF 2 α被血红素调节抑制激酶（HRI）磷酸化。HRI的消耗防止硼替佐米诱导的SGs形成并促进细胞凋亡。这是第一项描述化疗化合物形成SG的研究。我们推测HRI的激活和SGs的形成可能构成了癌细胞抵抗硼替佐米介导的凋亡的机制。
Cytoplasmic stress granules (SGs) are specialized storage sites of untranslated mRNAs whose formation occurs under different stress conditions and is often associated with cell survival. SGs-inducing stresses include radiations, hypoxia, viral infections, and chemical inhibitors of specific translation initiation factors. The FDA-approved drug bortezomib (Velcade®) is a peptide boronate inhibitor of the 26S proteasome that is very efficient for the treatment of myelomas and other hematological tumors. Solid tumors are largely refractory to bortezomib. In the present study, we investigated the formation of SGs following bortezomib treatment. We show that bortezomib efficiently induces the formation of SGs in cancer cells. This process involves the phosphorylation of translation initiation factor eIF2α by heme-regulated inhibitor kinase (HRI). Depletion of HRI prevents bortezomib-induced formation of SGs and promotes apoptosis. This is the first study describing the formation of SGs by a chemotherapeutic compound. We speculate that the activation of HRI and the formation of SGs might constitute a mechanism by which cancer cells resist bortezomib-mediated apoptosis.