Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL 32610, USA; UF-Health Cancer Center, University of Florida, Gainesville, FL 32610, USA.
Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
Crit Rev Oncol Hematol. 2018 Jul;127:66-79. doi: 10.1016/j.critrevonc.2018.05.003. Epub 2018 May 26.
The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells, responsible for protein synthesis, folding, sorting, and transportation. ER stress is initiated when the unfolded or misfolded protein load exceeds the capacity of the ER to properly fold protein. Tumor microenvironmental conditions, such as nutrient deprivation, hypoxia, and oxidative stress perturb protein folding and trigger chronic ER stress. Cancer cells can tolerate mild ER stress, however, persistent and severe ER stress kills cancer cells by inducing their autophagy, apoptosis, necroptosis, or immunogenic cell death. Based on this rationale, many drugs have been developed for triggering irremediable ER stress in cancer cells by targeting various processes in the secretory pathway. This review discusses the mechanisms of protein targeting to the ER, the key signaling cassettes that are involved in the ER stress response, and their correlation with cancer formation and progression. Importantly, this review discusses current experimental and FDA approved anti-cancer drugs that induce ER stress, and emerging targets within the secretory pathway for the development of new anticancer drugs.
内质网（ER）是真核细胞的一种重要细胞器，负责蛋白质的合成、折叠、分拣和运输。当未折叠或错误折叠的蛋白质负荷超过内质网正确折叠蛋白质的能力时，内质网应激就会启动。肿瘤微环境条件，如营养剥夺、缺氧和氧化应激，会破坏蛋白质折叠，并引发慢性内质网应激。然而，癌细胞可以耐受轻度的内质网应激，持续和严重的内质网应激通过诱导自噬、细胞凋亡、坏死性凋亡或免疫原性细胞死亡来杀死癌细胞。基于这一原理，许多药物已经被开发出来，通过靶向分泌途径中的各种过程，在癌细胞中引发不可挽回的内质网应激。本文讨论了蛋白质靶向内质网的机制、参与内质网应激反应的关键信号级联，以及它们与癌症形成和进展的相关性。重要的是，本文还讨论了目前诱导内质网应激的实验性和 FDA 批准的抗癌药物，以及分泌途径中用于开发新抗癌药物的新兴靶点。
