GEFT inhibits the GSDM-mediated proptosis signalling pathway, promoting the progression and drug resistance of rhabdomyosarcoma.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Fan Yang, Tian Xia, Zhijuan Zhao, Jinyang Lin, Ling Zhong, Tian Tang, Degui Liao, Miaoling Lai, Jiamin Ceng, Lian Meng, Feng Li, Chunxia Liu
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引用次数: 0

Abstract

The metastasis or recurrence of rhabdomyosarcoma (RMS) is the primary cause of tumour-related deaths. Patients with high-risk RMS have poor prognosis with a 5-year overall survival rate of 20-30%. The lack of specific drug-targeted therapy and chemotherapy resistance are the main reasons for treatment failure. Drugs or molecular target inhibitors can induce the pyroptosis of tumour cells or increase their sensitivity to chemotherapy, making pyroptosis an effective strategy for antitumour therapies. Pyroptosis is mediated by gasdermin (GSDM) family members. Here, we found that the expression of NLRP3, caspase-1, caspase-3, GSDMD and GSDME in RMS was remarkably lower than that in skeletal muscle tissues. Nigericin and dactinomycin in RMS cells achieved their regulatory effect on pyroptosis through the NLRP3/caspase-1/GSDMD pathway and caspase-3/GSDME pathway, respectively. Necrosulfonamide reversed the pyroptosis-related changes induced by nigericin, and siGSDME converted the dactinomycin-induced pyroptosis into apoptosis. Additionally, GEFT inhibited the GSDMD and GSDME pyroptosis pathways, thereby promoting the progression and drug resistance of RMS. Mouse xenograft and tumour analysis confirmed that nigericin and dactinomycin can effectively improve the therapeutic effect of RMS by activating the pyroptosis pathway. To the best of our knowledge, this study was the first to focus on pyroptosis in RMS. Overall, our investigation demonstrated that nigericin and dactinomycin play therapeutic roles in tumours by promoting RMS cell pyroptosis. Interference with GEFT and drug combination can exert a great inhibitory effect on tumours.

GEFT抑制gsdm介导的突起信号通路,促进横纹肌肉瘤的进展和耐药。
横纹肌肉瘤(RMS)的转移或复发是肿瘤相关死亡的主要原因。高危RMS患者预后较差,5年总生存率为20-30%。缺乏特异性药物靶向治疗和化疗耐药是导致治疗失败的主要原因。药物或分子靶标抑制剂可诱导肿瘤细胞焦亡或增加其对化疗的敏感性,使焦亡成为抗肿瘤治疗的有效策略。焦亡是由气皮蛋白(GSDM)家族成员介导的。我们发现NLRP3、caspase-1、caspase-3、GSDMD和GSDME在RMS中的表达明显低于骨骼肌组织。尼日利亚菌素和放线菌素分别通过NLRP3/caspase-1/GSDMD途径和caspase-3/GSDME途径实现对RMS细胞焦亡的调控作用。坏死性磺胺逆转了尼日利亚菌素诱导的热亡相关变化,siGSDME将放线菌素诱导的热亡转化为细胞凋亡。此外,GEFT抑制GSDMD和GSDME焦亡途径,从而促进RMS的进展和耐药。小鼠异种移植和肿瘤分析证实,尼古菌素和放线菌素可通过激活焦亡通路,有效提高RMS的治疗效果。据我们所知,这项研究是第一次关注RMS的焦亡。总之,我们的研究表明,尼日利亚菌素和放线菌素通过促进RMS细胞焦亡在肿瘤中发挥治疗作用。干涉GEFT和联合用药对肿瘤有很大的抑制作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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