Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy
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Abstract
Metabolic heterogeneity resulting from the intra-tumoral heterogeneity mediates massive adverse outcomes of tumor therapy, including chemotherapeutic resistance, but the mechanisms inside remain largely unknown. Here, we find that the de novo pyrimidine synthesis pathway determines the chemosensitivity. Chemotherapeutic drugs promote the degradation of cytosolic Carbamoyl-phosphate synthetase II, Aspartate transcarbamylase, and Dihydroorotase (CAD), an enzyme that is rate-limiting for pyrimidine synthesis, leading to apoptosis. We also find that CAD needs to be cleaved by caspase-3 on its Asp1371 residue, before its degradation. Overexpressing CAD or mutating Asp1371 to block caspase-3 cleavage confers chemoresistance in xenograft and Cldn18-ATK gastric cancer models. Importantly, mutations related to Asp1371 of CAD are found in tumor samples that failed neoadjuvant chemotherapy and pharmacological targeting of CAD-Asp1371 mutations using RMY-186 ameliorates chemotherapy efficacy. Our work reveals the vulnerability of de novo pyrimidine synthesis during chemotherapy, highlighting CAD as a promising therapeutic target and biomarker.
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Self-citation
- Authors
- Ma, J., Zhao, J., Zhang, C., Tan, J., Cheng, A., Niu, Z., Lin, Z., Pan, G., Chen, C., Ding, Y., Zhong, M., Zhuang, Y., Xiong, Y., Zhou, H., Zhou, S., Xu, M., Ye, W., Li, F., Song, Y., Wang, Z., & Hong, X.
- Affiliations
- Xiamen University (CN)
- First Hospital of China Medical University (CN)
- Corresponding author
- Song, Yongxi
- Wang, Zhenning
- Hong, Xuehui
- ORCID
- Venue
- Nature Communications
- Published
- 2025-05-30
- Volume
- 16
- Issue
- 1
- Pages
- 5006-5006
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12123037
- OpenAlex
- W4410842863
- Cited by
- 14
- References
- 85
- Citations by year
- 2026: 7 · 2025: 7
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82122046, 82072727, 82103160)
- the Young Top Talents of Fujian Young Eagle Project(/) and the Fujian Health Youth Scientific Research Project
- the International Science and Technology Cooperation Project of Liaoning Province
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- aspartate transcarbamylase, dihydroorotase, caspase-3 cleavage, de novo pyrimidine biosynthesis, chemoresistance, gastric cancer, apoptosis, tumor metabolic heterogeneity, neoadjuvant chemotherapy, therapeutic target, biomarkers
- MeSH terms
- Animals, Antineoplastic Agents, Aspartate Carbamoyltransferase, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Dihydroorotase, Female, Humans, Mutation, Pyrimidines, Stomach Neoplasms, Apoptosis, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Caspase 3
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