What question did this study set out to answer?

To investigate how targeting the de novo purine biosynthesis pathway affects esophageal squamous cell carcinoma growth.

April 5, 2026Cancer Research0 citations

Abstract 3042: Inhibition of de novo purine biosynthesis via PPAT targeting by cucurbitacin B restrains esophageal squamous cell carcinoma growth

MSMengqiu SongZhengzhou University JGJun li GuoZhengzhou University HJHuajie JiaZhengzhou University

Key Points

To investigate how targeting the de novo purine biosynthesis pathway affects esophageal squamous cell carcinoma growth.
Utilized untargeted metabolomics and single-cell RNA sequencing for metabolic analysis of ESCC.
Evaluated PPAT expression and function through immunohistochemistry and gene manipulation.
Used patient-derived and cell-derived xenograft models to study tumor growth and radioresistance.
Identified PPAT as a key player in ESCC malignancy by promoting energy-related nucleotide production.
Demonstrated that Cucurbitacin B targets PPAT, leading to its degradation and reduced tumor growth.
Showed that Cucurbitacin B enhances the effectiveness of radiotherapy in ESCC.

Abstract

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. Citation Format: Mengqiu Song, Jing Guo, Huajie Jia, Jie Tian, Pan Li, Zigang Dong. Inhibition of de novo purine biosynthesis via PPAT targeting by cucurbitacin B restrains esophageal squamous cell carcinoma growth abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3042.

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