HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells.
HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells.
复制标题
HRI 介导的翻译抑制可降低人胰腺癌细胞中的蛋白毒性和对硼替佐米的敏感性。
DOI：
10.1038/s41388-018-0227-y
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发表时间：
2018
期刊：
影响因子：
8
通讯作者：
McConkey,DavidJ
中科院分区：
文献类型：
--
作者：
White,MatthewC;Schroeder,RebeccaD;Zhu,Keyi;Xiong,Katherine;McConkey,DavidJ
人类癌细胞对蛋白酶体抑制剂硼替佐米（Velcade）的敏感性表现出广泛的异质性。这种异质性背后的分子机制仍不清楚，克服耐药性的策略也很有限。在这里，我们发现十种人类胰腺癌细胞系中 eIF2α 磷酸化的固有差异显着影响硼替佐米的敏感性，并暗示 HRI（血红素调节抑制剂）eIF2α 激酶作为一种新的治疗靶点。在我们的小组中，我们鉴定了一个细胞系子集，其 eIF2α 磷酸化诱导存在缺陷，从而赋予了硼替佐米高度的敏感性。这些硼替佐米敏感细胞表现出翻译衰减受损，随后蛋白质聚集体和活性氧 (ROS) 有毒积累，而硼替佐米耐药细胞系表现出 eIF2α 磷酸化增加、翻译减少、蛋白质聚集体很少和 ROS 产生最少。重要的是，我们确定 HRI 是主要的硼替佐米激活的 eIF2α 激酶，并证明 HRI 敲低可促进硼替佐米耐药细胞的细胞死亡。总体而言，我们的数据表明，HRI 介导的诱导型 eIF2α 磷酸化是硼替佐米暴露后的核心细胞保护机制，并为开发 HRI 抑制剂以克服蛋白酶体抑制剂耐药性提供了概念验证。
Human cancer cells display extensive heterogeneity in their sensitivities to the proteasome inhibitor bortezomib (Velcade). The molecular mechanisms underlying this heterogeneity remain unclear, and strategies to overcome resistance are limited. Here, we discover that inherent differences in eIF2α phosphorylation among a panel of ten human pancreatic cancer cell lines significantly impacts bortezomib sensitivity, and implicate the HRI (heme-regulated inhibitor) eIF2α kinase as a novel therapeutic target. Within our panel, we identified a subset of cell lines with defective induction of eIF2α phosphorylation, conferring a high degree of sensitivity to bortezomib. These bortezomib-sensitive cells exhibited impaired translation attenuation followed by toxic accumulation of protein aggregates and reactive oxygen species (ROS), whereas the bortezomib-resistant cell lines displayed increased phosphorylation of eIF2α, decreased translation, few protein aggregates, and minimal ROS production. Importantly, we identified HRI as the primary bortezomib-activated eIF2α kinase, and demonstrated that HRI knockdown promoted cell death in the bortezomib-resistant cells. Overall, our data implicate inducible HRI-mediated phosphorylation of eIF2α as a central cytoprotective mechanism following exposure to bortezomib and provide proof-of-concept for the development of HRI inhibitors to overcome proteasome inhibitor resistance.