OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universitat Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstr. 74, 01307 Dresden, Germany.
Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, Drahomanov Str. 14/16, Lviv 79005, Ukraine.
Curr Med Chem. 2018;25(21):2465-2502. doi: 10.2174/0929867325666180117110259.
The paradoxical role of ER stress in malignant diseases is only just being unraveled and remains incompletely understood. A particular challenge is the complex interplay between spaciotemporal and locoregional microenvironmental constraints in solid tumors and stress responses upon treatment; thus, the potential for new combinatorial therapeutic options to foster the coincidence of ER stress-related deadly events is likely to be underestimated. Without claiming this review to be complete, we present a comprehensive overview of the signaling mechanisms associated with the unfolded protein response (UPR) and the molecular link to cell survival and death mechanisms. We (i) delineate the mechanistic scenario and outcome of the UPR; (ii) discuss the role of ER stress in cancer development and progression; (iii) highlight the impact of various environmental conditions and stress stimuli, such as nutrient limitation and tumor hypoxia, in this context; and (iv) attempt to shed some light on the putative link between DNA damage, irradiation, and ER stress to emphasize the potential of therapeutic targeting of ER stress pathways for combined cancer treatments.
内质网应激在恶性疾病中的矛盾作用才刚刚被揭示出来，目前仍不完全清楚。一个特别的挑战是实体瘤中时空和局部微环境限制与治疗时应激反应之间的复杂相互作用；因此，促进内质网应激相关致命事件同时发生的新组合治疗选择的潜力可能被低估。我们在此不声称这篇综述是完整的，而是提供了与未折叠蛋白反应（UPR）相关的信号转导机制以及与细胞存活和死亡机制的分子联系的全面概述。我们：（i）描绘 UPR 的机制情况和结果；（ii）讨论内质网应激在癌症发展和进展中的作用；（iii）强调各种环境条件和应激刺激（如营养限制和肿瘤缺氧）在这方面的影响；（iv）试图阐明 DNA 损伤、辐射和内质网应激之间的潜在联系，以强调针对内质网应激途径的治疗靶向在联合癌症治疗中的潜力。
