School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China.
Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730030, China.
Radiother Oncol. 2024 Nov;200:110528. doi: 10.1016/j.radonc.2024.110528. Epub 2024 Sep 7.
Radioresistance is a significant challenge in the radiotherapy of non-small cell lung cancer (NSCLC). This study aimed to investigate the role of R-spondin 3 (RSPO3) in regulating NSCLC radioresistance.
RNA sequencing was performed to analyze genes that are differentially expressed in radioresistant NSCLC cell lines. RSPO3 overexpression and knockdown experiments were conducted to assess its impact on radiosensitivity. The involvement of the β-catenin-NF-κB signaling pathway and the NLRP3 inflammasome in RSPO3-mediated radiosensitivity was also evaluated. In vivo experiments were conducted using a clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) to assess its impact on radiation-induced pyroptosis and subsequent anti-tumor immunity.
RSPO3 expression was downregulated in radioresistant NSCLC cells. Overexpression of RSPO3 increased NSCLC radiosensitivity through the induction of pyroptosis, which was mediated by the β-catenin-NF-κB signaling pathway and the NLRP3 inflammasome. The anti-RSPO3 antibody effectively blocked radiation-induced pyroptosis and anti-tumor immunity in vivo. Conversely, upregulation of RSPO3 enhanced NSCLC tumor radiosensitivity.
The findings demonstrated that RSPO3 plays a crucial role in regulating NSCLC radioresistance via NLRP3 mediated pyroptosis. Targeting the RSPO3-NLRP3 inflammasome axis may offer a potential therapeutic strategy to enhance the efficacy of radiotherapy for NSCLC patients.
放射抵抗是非小细胞肺癌（NSCLC）放射治疗的重大挑战。本研究旨在探讨 R 脊椎蛋白 3（RSPO3）在调节 NSCLC 放射抵抗中的作用。
采用 RNA 测序分析放射抵抗 NSCLC 细胞系中差异表达的基因。进行 RSPO3 过表达和敲低实验，评估其对放射敏感性的影响。还评估了β-catenin-NF-κB 信号通路和 NLRP3 炎性体在 RSPO3 介导的放射敏感性中的参与。使用临床级抗 RSPO3 抗体（OMP-131R10/rosmantuzumab）进行体内实验，评估其对放射诱导的细胞焦亡及其随后的抗肿瘤免疫的影响。
RSPO3 在放射抵抗 NSCLC 细胞中表达下调。RSPO3 的过表达通过诱导细胞焦亡增加 NSCLC 的放射敏感性，这是通过 β-catenin-NF-κB 信号通路和 NLRP3 炎性体介导的。抗 RSPO3 抗体可有效阻断体内放射诱导的细胞焦亡和抗肿瘤免疫。相反，RSPO3 的上调增强了 NSCLC 肿瘤的放射敏感性。
研究结果表明，RSPO3 通过 NLRP3 介导的细胞焦亡在调节 NSCLC 放射抵抗中发挥关键作用。靶向 RSPO3-NLRP3 炎性体轴可能为增强 NSCLC 患者放射治疗的疗效提供一种潜在的治疗策略。
