Departments of Pharmacology and Medicine, Section of Hematology and Medical Oncology, Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA.
Crit Rev Biochem Mol Biol. 2020 Aug;55(4):322-353. doi: 10.1080/10409238.2020.1784085. Epub 2020 Jul 7.
During malignant transformation and cancer progression, tumor cells face both intrinsic and extrinsic stress, endoplasmic reticulum (ER) stress in particular. To survive and proliferate, tumor cells use multiple stress response pathways to mitigate ER stress, promoting disease aggression and treatment resistance. Among the stress response pathways is ER-associated degradation (ERAD), which consists of multiple components and steps working together to ensure protein quality and quantity. In addition to its established role in stress responses and tumor cell survival, ERAD has recently been shown to regulate tumor immunity. Here we summarize current knowledge on how ERAD promotes protein degradation, regulates immune cell development and function, participates in antigen presentation, exerts paradoxical roles on tumorigenesis and immunity, and thus impacts current cancer therapy. Collectively, ERAD is a critical protein homeostasis pathway intertwined with cancer development and tumor immunity. Of particular importance is the need to further unveil ERAD's enigmatic roles in tumor immunity to develop effective targeted and combination therapy for successful treatment of cancer.
在恶性转化和癌症进展过程中，肿瘤细胞面临内在和外在的压力，特别是内质网（ER）应激。为了生存和增殖，肿瘤细胞利用多种应激反应途径来减轻 ER 应激，促进疾病侵袭和治疗耐药。应激反应途径之一是 ER 相关降解（ERAD），它由多个组件和步骤共同作用，以确保蛋白质的质量和数量。除了在应激反应和肿瘤细胞存活中的既定作用外，ERAD 最近还被证明可以调节肿瘤免疫。在这里，我们总结了 ERAD 促进蛋白质降解、调节免疫细胞发育和功能、参与抗原呈递、对肿瘤发生和免疫产生矛盾作用以及因此影响当前癌症治疗的最新知识。总的来说，ERAD 是一个关键的蛋白质动态平衡途径，与癌症的发展和肿瘤免疫交织在一起。特别重要的是，需要进一步揭示 ERAD 在肿瘤免疫中的神秘作用，以开发有效的靶向和联合治疗方法，成功治疗癌症。
