Oncogenesis, Stress, Cancer, University of Rennes, Rennes, France. Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile. Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, Santiago, Chile. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts.
Cancer Discov. 2015 Jun;5(6):586-97. doi: 10.1158/2159-8290.CD-14-1490. Epub 2015 May 14.
Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is observed in many human diseases, including cancers. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. The UPR has emerged as a major pathway in remodeling cancer gene expression, thereby either preventing cell transformation or providing an advantage to transformed cells. UPR sensors are highly regulated by the formation of dynamic protein scaffolds, leading to integrated reprogramming of the cells. Herein, we describe the regulatory mechanisms underlying UPR signaling upon cell intrinsic or extrinsic challenges, and how they engage cell transformation programs and/or provide advantages to cancer cells, leading to enhanced aggressiveness or chemoresistance. We discuss the emerging cross-talk between the UPR and related metabolic processes to ensure maintenance of protein homeostasis and its impact on cell transformation and tumor growth.
ER stress signaling is dysregulated in many forms of cancer and contributes to tumor growth as a survival factor, in addition to modulating other disease-associated processes, including cell migration, cell transformation, and angiogenesis. Evidence for targeting the ER stress signaling pathway as an anticancer strategy is compelling, and novel agents that selectively inhibit the UPR have demonstrated preliminary evidence of preclinical efficacy with an acceptable safety profile.
内质网（ER）中未折叠蛋白的积累所导致的应激在许多人类疾病中都有观察到，包括癌症。细胞对 ER 应激的适应是由未折叠蛋白反应（UPR）介导的，其目的是恢复 ER 稳态。UPR 已成为重塑癌症基因表达的主要途径，从而防止细胞转化或为转化细胞提供优势。UPR 传感器受到动态蛋白质支架形成的高度调节，导致细胞的综合重编程。在此，我们描述了细胞内在或外在挑战时 UPR 信号转导的调节机制，以及它们如何参与细胞转化程序和/或为癌细胞提供优势，从而增强侵袭性或化疗耐药性。我们讨论了 UPR 与相关代谢过程之间新兴的交叉对话，以确保蛋白质稳态的维持及其对细胞转化和肿瘤生长的影响。
内质网应激信号在许多形式的癌症中失调，除了调节其他与疾病相关的过程（包括细胞迁移、细胞转化和血管生成）外，它还是一种生存因素，促进肿瘤生长。作为一种抗癌策略，靶向 ER 应激信号通路的证据令人信服，并且新型选择性抑制 UPR 的药物已显示出初步的临床前疗效，具有可接受的安全性。
