PO.ET09.09 · 实验与分子治疗
葫芦素 B 通过靶向 PPAT 抑制从头嘌呤生物合成从而遏制食管鳞状细胞癌生长
Inhibition of d e novo purine biosynthesis via PPAT targeting by cucurbitacin B restrains esophageal squamous cell carcinoma growth
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：从头嘌呤生物合成（DNPB）通路在肿瘤的恶性进展中发挥关键作用。然而，它对食管鳞状细胞癌（ESCC）生长、放射抗性及靶向治疗反应的具体贡献仍知之甚少。
方法：在本研究中，通过非靶向代谢组学和单细胞 RNA 测序数据分析对 ESCC 的潜在代谢改变进行了分析。进一步通过免疫组化（IHC）和慢病毒介导的基因操作评估了 PPAT 的表达和功能。此外，利用患者来源异种移植（PDX）和细胞来源异种移植（CDX）模型评估了 PPAT 及其抑制剂在 ESCC 肿瘤生长和放射抗性中的作用。
结果：在本研究中，我们将磷酸核糖焦磷酸酰胺转移酶（PPAT）——DNPB 通路中的一个关键限速酶——确定为 ESCC 恶性程度的关键调节因子。我们证明 PPAT 促进能量相关核苷酸（包括 AMP、GMP、ADP、GDP、ATP 和 GTP）的生成，从而在体外和体内为 ESCC 肿瘤生长提供动力。此外，我们发现葫芦素 B（CuB）特异性靶向 PPAT，并通过 E3 连接酶 TRIM38 诱导其多聚泛素介导的降解，导致 DNPB 通路受抑制和肿瘤生长受抑制。重要的是，CuB 还作为放射增敏剂发挥作用，显著增强了放疗对 ESCC 的治疗疗效。
结论：我们的发现揭示，靶向 PPAT 代表了一种有前景的治疗策略，可抑制 ESCC 进展并增强放疗疗效。
查看英文原文 English abstract
Background: The de novo purine biosynthesis (DNPB) pathway plays a critical role in the malignant progression of tumors. However, its specific contribution to esophageal squamous cell carcinoma (ESCC) growth, radioresistance, and response to targeted therapies remains poorly understood.
Methods: In this study, the underlying metabolic change of ESCC were analyzed by untargeted metabolomics and single-cell RNA sequencing data analyses. The expression and function of PPAT were further evaluated through immunohistochemistry (IHC) and lentivirus-mediated gene manipulation. Additionally, patient-derived xenograft (PDX) and cell-derived xenograft (CDX) models were utilized to assess the role of PPAT and its inhibitor in ESCC tumor growth and radioresistance.
Results: In this study, we identified phosphoribosyl pyrophosphate amidotransferase (PPAT), a key rate-limiting enzyme in the DNPB pathway, as a critical modulator of ESCC malignancy. We demonstrated that PPAT promotes the production of energy-related nucleotides, including AMP, GMP, ADP, GDP, ATP, and GTP, thereby fueling ESCC tumor growth in vitro and in vivo. Moreover, we found that Cucurbitacin B (CuB) specifically targets PPAT and induces its polyubiquitin-mediated degradation via the E3 ligase TRIM38, leading to suppression of the DNPB pathway and inhibition of tumor growth. Importantly, CuB also functions as a radiosensitizer, significantly enhancing the therapeutic efficacy of radiotherapy in ESCC.
Conclusions: Our findings reveal that targeting PPAT represents a promising therapeutic strategy to suppress ESCC progression and enhance the efficacy of radiotherapy.
利益披露 Disclosure
M. Song, None..
J. Guo, None..
H. Jia, None..
J. Tian, None..
P. Li, None..
Z. Dong, None.