McConkey David J
Johns Hopkins Greenberg Bladder Cancer Institute, Brady Urological Institute, 600 North Wolfe Street, Baltimore, MD 21287, United States.
Biochem Biophys Res Commun. 2017 Jan 15;482(3):450-453. doi: 10.1016/j.bbrc.2016.11.047. Epub 2017 Feb 3.
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.
多种不同形式的细胞应激可导致蛋白质错误折叠、聚集及蛋白毒性。针对蛋白毒性的细胞保护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，它们作用于翻译起始因子eIF2α，导致其第51位丝氨酸磷酸化、细胞周期停滞，并全面抑制整体蛋白质合成。eIF2α的磷酸化还促进ATF4的翻译以及ATF4靶基因的表达，这些靶基因可改善蛋白毒性应激，但也可促进细胞凋亡。本综述简要概述了这些机制，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型癌症治疗药物，通过蛋白毒性应激促进肿瘤细胞死亡。
