Cao Shulong, Tang Jingyi, Huang Yichun, Li Gaofeng, Li Zhuoya, Cai Wenqi, Yuan Yuning, Liu Junlong, Huang Xuqun, Zhang Haiyuan
School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China.
Clinical Medical College, Hubei University of Science and Technology, Xianning, China.
Front Mol Biosci. 2021 Apr 13;8:620514. doi: 10.3389/fmolb.2021.620514. eCollection 2021.
Endoplasmic reticulum stress (ERS), which refers to a series of adaptive responses to the disruption of endoplasmic reticulum (ER) homeostasis, occurs when cells are treated by drugs or undergo microenvironmental changes that cause the accumulation of unfolded/misfolded proteins. ERS is one of the key responses during the drug treatment of solid tumors. Drugs induce ERS by reactive oxygen species (ROS) accumulation and Ca overload. The unfolded protein response (UPR) is one of ERS. Studies have indicated that the mechanism of ERS-mediated drug resistance is primarily associated with UPR, which has three main sensors (PERK, IRE1α, and ATF6). ERS-mediated drug resistance in solid tumor cells is both intrinsic and extrinsic. Intrinsic ERS in the solid tumor cells, the signal pathway of UPR-mediated drug resistance, includes apoptosis inhibition signal pathway, protective autophagy signal pathway, ABC transporter signal pathway, Wnt/β-Catenin signal pathway, and noncoding RNA. Among them, apoptosis inhibition is one of the major causes of drug resistance. Drugs activate ERS and its downstream antiapoptotic proteins, which leads to drug resistance. Protective autophagy promotes the survival of solid tumor cells by devouring the damaged organelles and other materials and providing new energy for the cells. ERS induces protective autophagy by promoting the expression of autophagy-related genes, such as Beclin-1 and ATG5-ATG12. ABC transporters pump drugs out of the cell, which reduces the drug-induced apoptosis effect and leads to drug resistance. In addition, the Wnt/β-catenin signal pathway is also involved in the drug resistance of solid tumor cells. Furthermore, noncoding RNA regulates the ERS-mediated survival and death of solid tumor cells. Extrinsic ERS in the solid tumor cells, such as ERS in immune cells of the tumor microenvironment (TME), also plays a crucial role in drug resistance by triggering immunosuppression. In immune system cells, ERS in dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) influences the antitumor function of normal T cells, which results in immunosuppression. Meanwhile, ERS in T cells can also cause impaired functioning and apoptosis, leading to immunosuppression. In this review, we highlight the core molecular mechanism of drug-induced ERS involved in drug resistance, thereby providing a new strategy for solid tumor treatment.
内质网应激（ERS）是指细胞对内质网（ER）稳态破坏的一系列适应性反应，当细胞受到药物处理或经历导致未折叠/错误折叠蛋白质积累的微环境变化时就会发生。ERS是实体瘤药物治疗过程中的关键反应之一。药物通过活性氧（ROS）积累和钙超载诱导ERS。未折叠蛋白反应（UPR）是ERS的一种。研究表明，ERS介导的耐药机制主要与UPR相关，UPR有三个主要传感器（PERK、IRE1α和ATF6）。实体瘤细胞中ERS介导的耐药既有内在因素也有外在因素。实体瘤细胞中的内在ERS，即UPR介导的耐药信号通路，包括凋亡抑制信号通路、保护性自噬信号通路、ABC转运蛋白信号通路、Wnt/β-连环蛋白信号通路和非编码RNA。其中，凋亡抑制是耐药的主要原因之一。药物激活ERS及其下游抗凋亡蛋白，从而导致耐药。保护性自噬通过吞噬受损细胞器和其他物质并为细胞提供新能量来促进实体瘤细胞的存活。ERS通过促进自噬相关基因（如Beclin-1和ATG5-ATG12）的表达来诱导保护性自噬。ABC转运蛋白将药物泵出细胞，这降低了药物诱导的凋亡效应并导致耐药。此外，Wnt/β-连环蛋白信号通路也参与实体瘤细胞的耐药。此外，非编码RNA调节ERS介导的实体瘤细胞存活和死亡。实体瘤细胞中的外在ERS，如肿瘤微环境（TME）免疫细胞中的ERS，也通过触发免疫抑制在耐药中起关键作用。在免疫系统细胞中，树突状细胞（DCs）和髓源性抑制细胞（MDSCs）中的ERS影响正常T细胞的抗肿瘤功能，从而导致免疫抑制。同时，T细胞中的ERS也可导致功能受损和凋亡，导致免疫抑制。在本综述中，我们强调了药物诱导的ERS参与耐药的核心分子机制，从而为实体瘤治疗提供了新策略。
