METHODS: Cell viability assay, RT-qPCR, Colony formation assay, Western blot, and Xenogeneic transplantation methods were used to investigate roles and mechanisms of IRE1α/XBP1s pathway in the paclitaxel-resistant TNBC cells, and combined paclitaxel and IRE1α inhibitor in the treatment of TNBC was examined in vitro and in vivo.
RESULTS: We found activation of UPR in paclitaxel-resistant cells, confirming that IRE1α/XBP1 promotes paclitaxel resistance in TNBC. In addition, we demonstrated that the combination of paclitaxel and IRE1α inhibitors can synergistically inhibit the proliferation of TNBC tumors both in vitro and in vivo,suggesting that IRE1α inhibitors combined with paclitaxel may be a new treatment option for TNBC.
CONCLUSIONS: In this study, we demonstrated the important role of IRE1α signaling in mediating paclitaxel resistance and identified that combination therapies targeting IRE1α signaling could overcome paclitaxel resistance and enhance chemotherapy efficacy.
方法:细胞活力测定,RT-qPCR,集落形成测定,蛋白质印迹,采用异种移植方法研究IRE1α/XBP1s通路在紫杉醇耐药TNBC细胞中的作用及机制,并在体外和体内检查了紫杉醇和IRE1α抑制剂联合治疗TNBC的作用。
结果:我们在紫杉醇耐药细胞中发现了UPR的激活,证实IRE1α/XBP1促进TNBC的紫杉醇耐药。此外,我们证明了紫杉醇和IRE1α抑制剂的联合使用可以在体外和体内协同抑制TNBC肿瘤的增殖,提示IRE1α抑制剂联合紫杉醇可能是TNBC的新治疗选择。
结论:在这项研究中,我们证明了IRE1α信号传导在介导紫杉醇耐药中的重要作用,并确定靶向IRE1α信号传导的联合治疗可以克服紫杉醇耐药并增强化疗疗效.