Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER,, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide,, Avda Américo Vespucio 24,, 41092, Sevilla,, Spain.
Departament de Ciencies Fisiologiques, Facultat de Medicina i Ciencies de la Salut, Universitat de Barcelona-IDIBELL (Institut d'Investigacio Biomedica de Bellvitge), L'Hospitalet de Llobregat, Barcelona, Spain.
Cell Death Dis. 2018 Jan 26;9(2):134. doi: 10.1038/s41419-017-0164-7.
Recent evidences indicate that triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype show a basal activation of the unfolded protein response (UPR) that increases their sensitivity to endoplasmic reticulum (ER) stress although the underlying cell death mechanism remains largely unexplored. Here we show that both caspase-8-dependent and -independent apoptotic mechanisms are activated in TNBC cells undergoing sustained ER stress. Activation of the extrinsic apoptotic pathway by ER stress involves ATF4-dependent upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5). In addition, accumulation of BH3-only protein Noxa at the mitochondria further contributes to apoptosis following ER stress in TNBC cells. Accordingly, simultaneous abrogation of both extrinsic and intrinsic apoptotic pathways is required to inhibit ER stress-induced apoptosis in these cells. Importantly, persistent FLICE-inhibitory protein (FLIP) expression plays an adaptive role to prevent early activation of the extrinsic pathway of apoptosis upon ER stress. Overall, our data show that ER stress induces cell death through a pleiotropic mechanism in TNBC cells and suggest that targeting FLIP expression may be an effective approach to sensitize these tumor cells to ER stress-inducing agents.
最近的证据表明，具有间充质表型的三阴性乳腺癌（TNBC）细胞表现出未折叠蛋白反应（UPR）的基础激活，尽管潜在的细胞死亡机制在很大程度上仍未得到探索，但这增加了它们对内质网（ER）应激的敏感性。在这里，我们表明，在经历持续 ER 应激的 TNBC 细胞中， caspase-8 依赖性和非依赖性凋亡机制都被激活。ER 应激引发的细胞外凋亡途径的激活涉及 ATF4 依赖性肿瘤坏死因子相关凋亡诱导配体受体 2（TRAIL-R2/DR5）的上调。此外，BH3 仅蛋白 Noxa 在 ER 应激后在线粒体中的积累进一步促进了 TNBC 细胞的凋亡。因此，需要同时阻断细胞外和细胞内凋亡途径，才能抑制这些细胞中 ER 应激诱导的凋亡。重要的是，持续的 FLICE 抑制蛋白（FLIP）表达在 ER 应激时对细胞外凋亡途径的早期激活起着适应性作用。总体而言，我们的数据表明，ER 应激通过 TNBC 细胞中的多效性机制诱导细胞死亡，并表明靶向 FLIP 表达可能是一种有效的方法，可使这些肿瘤细胞对 ER 应激诱导剂敏感。
