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PTRF/cavin
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AbstractBackgroundMetabolism remodeling is a hallmark of glioblastoma (GBM) that regulates tumor proliferation and the immune microenvironment. Previous studies have reported that increased polymerase 1 and transcript release factor (PTRF) levels are associated with a worse prognosis in glioma patients. However, the biological role and the molecular mechanism of PTRF in GBM metabolism remain unclear.MethodsThe relationship between PTRF and lipid metabolism in GBM was detected by nontargeted metabolomics profiling and subsequent lipidomics analysis. Western blotting, quantitative real-time PCR, and immunoprecipitation were conducted to explore the molecular mechanism of PTRF in lipid metabolism. A sequence of in vitro and in vivo experiments (both xenograft tumor and intracranial tumor mouse models) were used to detect the tumor-specific impacts of PTRF.ResultsHere, we show that PTRF triggers a cytoplasmic phospholipase A2 (cPLA2)–mediated phospholipid remodeling pathway that promotes GBM tumor proliferation and suppresses tumor immune responses. Research in primary cell lines from GBM patients revealed that cells overexpressing PTRF show increased cPLA2 activity—resulting from increased protein stability—and exhibit remodeled phospholipid composition. Subsequent experiments revealed that PTRF overexpression alters the endocytosis capacity and energy metabolism of GBM cells. Finally, in GBM xenograft and intracranial tumor mouse models, we showed that inhibiting cPLA2 activity blocks tumor proliferation and prevents PTRF-induced reduction in CD8+ tumor-infiltrating lymphocytes.ConclusionsThe PTRF-cPLA2 lipid remodeling pathway promotes tumor proliferation and suppresses immune responses in GBM. In addition, our findings highlight multiple new therapeutic targets for GBM.
中文翻译：
摘要背景代谢重塑是调节肿瘤增殖和免疫微环境的胶质母细胞瘤 (GBM) 的标志。先前的研究报告称，增加的聚合酶 1 和转录物释放因子 (PTRF) 水平与胶质瘤患者的预后较差有关。然而，PTRF 在 GBM 代谢中的生物学作用和分子机制尚不清楚。方法通过非靶向代谢组学分析和随后的脂质组学分析检测 PTRF 与 GBM 中脂质代谢之间的关系。进行蛋白质印迹、实时定量 PCR 和免疫沉淀以探索 PTRF 在脂质代谢中的分子机制。一系列体外和体内实验（异种移植肿瘤和颅内肿瘤小鼠模型）用于检测 PTRF 的肿瘤特异性影响。结果在这里，我们显示 PTRF 触发细胞质磷脂酶 A2 (cPLA2) 介导的磷脂重塑途径，促进 GBM 肿瘤增殖并抑制肿瘤免疫反应。对来自 GBM 患者的原代细胞系的研究表明，过表达 PTRF 的细胞显示出 cPLA2 活性增加——这是由于蛋白质稳定性增加——并表现出重塑的磷脂成分。随后的实验表明，PTRF 过表达改变了 GBM 细胞的内吞能力和能量代谢。最后，在 GBM 异种移植物和颅内肿瘤小鼠模型中，我们发现抑制 cPLA2 活性可阻断肿瘤增殖并防止 PTRF 诱导的 CD8+ 肿瘤浸润淋巴细胞减少。结论PTRF-cPLA2 脂质重塑途径促进肿瘤增殖并抑制 GBM 中的免疫反应。此外，我们的发现突出了 GBM 的多个新治疗靶点。 |
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