Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China.
West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China.
Free Radic Biol Med. 2023 Jun;202:110-120. doi: 10.1016/j.freeradbiomed.2023.03.027. Epub 2023 Mar 29.
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.
泛素-蛋白酶体系统功能障碍可诱导持续的内质网应激（ERS）和随后的细胞死亡。然而，恶性细胞已经进化出多种机制来逃避持续的 ERS。因此，鉴定肿瘤细胞对 ERS 产生抗性的机制对于利用这些细胞治疗耐药肿瘤具有重要意义。在此，我们发现蛋白酶体抑制剂可诱导 ERS，激活铁死亡信号，从而诱导肿瘤细胞对 ERS 的适应性耐受。机制上，铁死亡信号的激活被发现可促进包含错误折叠和未折叠蛋白的外泌体的形成和分泌，从而挽救 ERS 并促进肿瘤细胞存活。铁死亡信号的抑制与硼替佐米（一种临床使用的蛋白酶体抑制剂）协同作用，抑制体外和体内肝癌细胞的活力。本研究结果表明，ERS 耐药性可由 ERS-铁死亡信号-外泌体通路驱动，并对细胞内信号、内质网稳态和耐药性癌症治疗具有重要的临床意义。
