The integrated stress response and proteotoxicity in cancer therapy.
The integrated stress response and proteotoxicity in cancer therapy.
复制标题
DOI：
10.1016/j.bbrc.2016.11.047
复制
发表时间：
2017-01-15
影响因子：
3.1
通讯作者：
McConkey DJ
中科院分区：
文献类型：
--
作者：
McConkey DJ
多种不同形式的细胞应激可引起蛋白质错误折叠和聚集以及蛋白质毒性。对蛋白毒性的细胞保护性反应被称为综合应激反应，涉及4种不同的丝氨酸/苏氨酸蛋白激酶，这些蛋白激酶聚集在翻译起始因子eIF 2 α上，导致S51磷酸化、细胞周期停滞和整体蛋白合成的一般抑制。eIF 2 α的磷酸化还促进ATF 4的翻译和ATF 4靶基因的表达，从而改善蛋白毒性应激，但也可促进细胞凋亡。这篇小型综述提供了这些机制的一般概述，并讨论了涉及它们的肿瘤间异质性如何影响对蛋白酶体抑制剂的敏感性和耐药性，蛋白酶体抑制剂是一类新的癌症治疗药物，通过蛋白毒性应激促进肿瘤细胞杀伤。
A variety of different forms of cellular stress can cause protein misfolding and aggregation and proteotoxicity. The cytoprotective response to proteotoxicity is termed the integrated stress response and involves 4 distinct serine/threonine protein kinases that converge on the translation initiation factor eIF2α, resulting in phosphorylation at S51, cell cycle arrest, and a general inhibition of global protein synthesis. Phosphorylation of eIF2α also promotes translation of ATF4 and the expression of ATF4 target genes that ameliorate proteotoxic stress but can also promote apoptosis. This mini review provides a general overview of these mechanisms and discusses how the inter-tumor heterogeneity that involves them affects sensitivity and resistance to proteasome inhibitors, a new class of cancer therapeutics that promotes tumor cell killing via proteotoxic stress.