未折叠蛋白反应
蛋白酶体
微泡
内质网
细胞生物学
硼替佐米
癌症研究
信号转导
外体
程序性细胞死亡
细胞信号
分泌物
癌细胞
蛋白质稳态
生物
细胞凋亡
癌症
免疫学
小RNA
生物化学
基因
遗传学
多发性骨髓瘤
作者
Jian Yang,Huanji Xu,Wanlong Wu,Huixi Huang,Chenliang Zhang,Weiping Tang,Qinlin Tang,Feng Bi
标识
DOI:10.1016/j.freeradbiomed.2023.03.027
摘要
Dysfunction of the ubiquitin‒proteasome system can induce sustained endoplasmic reticulum stress (ERS) and subsequent cell death. However, malignant cells have evolved multiple mechanisms to evade sustained ERS. Therefore, identification of the mechanisms through which tumor cells develop resistance to ERS is important for the therapeutic exploitation of these cells for drug-resistant tumors. Herein, we found that proteasome inhibitors could induce ERS, activate ferroptosis signaling, and thereby induce the adaptive tolerance of tumor cells to ERS. Mechanistically, the activation of ferroptosis signaling was found to promote the formation and secretion of exosomes containing misfolded and unfolded proteins, which resulted in rescuing ERS and promoting tumor cell survival. The inhibition of ferroptosis signaling synergized with bortezomib, a clinically used proteasome inhibitor, to suppress the viability of hepatocellular carcinoma cells in vitro and in vivo. The present findings reveal that ERS resistance can be driven by an ERS-ferroptosis signaling-exosome pathway and have important clinical implications for intracellular signaling, ER homeostasis and drug-resistant cancer therapy.
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