Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Avda Américo Vespucio 24, 41092 Sevilla, Spain.
Int J Mol Sci. 2022 Aug 12;23(16):8987. doi: 10.3390/ijms23168987.
The uncontrolled proliferation of malignant cells in growing tumors results in the generation of different stressors in the tumor microenvironment, such as nutrient shortage, hypoxia and acidosis, among others, that disrupt endoplasmic reticulum (ER) homeostasis and may lead to ER stress. As a response to ER stress, both normal and tumor cells launch a set of signaling pathways known as the unfolded protein response (UPR) to restore ER proteostasis and maintain cell viability and function. However, under sustained ER stress, an apoptotic cell death process can be induced and this has been the subject of different review articles, although the role of the TRAIL-R2/DR5-activated extrinsic pathway of apoptosis has not yet been thoroughly summarized. In this Review, we provide an updated overview of the molecular mechanisms regulating cell fate decisions in tumor cells undergoing ER stress and discuss the role of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) in the final outcome of UPR signaling. Particularly, we focus on the mechanisms controlling cellular FLICE-like inhibitory protein (FLIP) levels in tumor cells undergoing ER stress, which may represent a potential target for therapeutic intervention in cancer.
在生长中的肿瘤中，恶性细胞的不受控制的增殖导致肿瘤微环境中产生不同的应激源，例如营养物质短缺、缺氧和酸中毒等，这些应激源破坏内质网（ER）的内稳态，并可能导致 ER 应激。作为对 ER 应激的反应，正常细胞和肿瘤细胞都会启动一系列被称为未折叠蛋白反应（UPR）的信号通路，以恢复 ER 蛋白平衡并维持细胞活力和功能。然而，在持续的 ER 应激下，可能会诱导细胞凋亡，这已经是不同综述文章的主题，尽管 TRAIL-R2/DR5 激活的细胞外凋亡途径的作用尚未得到彻底总结。在这篇综述中，我们提供了一个关于 ER 应激下肿瘤细胞命运决定的分子机制的最新概述，并讨论了肿瘤坏死因子（TNF）相关凋亡诱导配体受体 2（TRAIL-R2/DR5）在 UPR 信号转导的最终结果中的作用。特别地，我们专注于控制肿瘤细胞 ER 应激时细胞 FLICE 样抑制蛋白（FLIP）水平的机制，这可能代表癌症治疗干预的潜在靶点。
