Szaflarski Witold, Fay Marta M, Kedersha Nancy, Zabel Maciej, Anderson Paul, Ivanov Pavel
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Oncotarget. 2016 May 24;7(21):30307-22. doi: 10.18632/oncotarget.8728.
Resistance to chemotherapy drugs is a serious therapeutic problem and its underlying molecular mechanisms are complex. Stress granules (SGs), cytoplasmic ribonucleoprotein complexes assembled in cells exposed to stress, are implicated in various aspects of cancer cell metabolism and survival. SGs promote the survival of stressed cells by reprogramming gene expression and inhibiting pro-apoptotic signaling cascades. We show that the vinca alkaloid (VA) class of anti-neoplastic agents potently activates a SG-mediated stress response program. VAs inhibit translation initiation by simultaneous activation of eIF4E-BP1 and phosphorylation of eIF2α, causing polysome disassembly and SG assembly. VA-induced SGs contain canonical SG components but lack specific signaling molecules. Blocking VA-induced SG assembly by inactivating eIF4EBP1 or inhibiting eIF2α phosphorylation decreases cancer cell viability and promotes apoptosis. Our data describe previously unappreciated effects of VAs on cellular RNA metabolism and illuminate the roles of SGs in cancer cell survival.
对化疗药物的耐药性是一个严重的治疗问题，其潜在的分子机制很复杂。应激颗粒（SGs）是在受到应激的细胞中组装的细胞质核糖核蛋白复合物，与癌细胞代谢和存活的各个方面有关。应激颗粒通过重新编程基因表达和抑制促凋亡信号级联反应来促进应激细胞的存活。我们发现，长春花生物碱（VA）类抗肿瘤药物能有效激活应激颗粒介导的应激反应程序。长春花生物碱通过同时激活eIF4E-BP1和使eIF2α磷酸化来抑制翻译起始，导致多核糖体解体和应激颗粒组装。长春花生物碱诱导的应激颗粒含有典型的应激颗粒成分，但缺乏特定的信号分子。通过使eIF4EBP1失活或抑制eIF2α磷酸化来阻断长春花生物碱诱导的应激颗粒组装，可降低癌细胞活力并促进细胞凋亡。我们的数据描述了长春花生物碱对细胞RNA代谢的前所未有的影响，并阐明了应激颗粒在癌细胞存活中的作用。
