ArticleNature communications2025
Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- OTUD6A promotes de novo pyrimidine synthesis by deubiquitinating and stabilizing CAD in cervical cancer.Oncogene · 2026Article
- A Triple-Stage Precision Carbon Dot Nanogel With Cascade Activation for Spatiotemporally Controlled Chemo-Photodynamic Therapy.Advanced healthcare materials · 2026Article
- Mechano-matching hydrogel patch promotes myocardial infarction repair via YAP-Bcl-2 pathway activation.Materials today. Bio · 2026Article
- Article
- Glutamine metabolism and its roles in tumor radiotherapy by regulating DNA damage repair.Frontiers in cell and developmental biology · 2026Review
- Targeting CAD with a tumor microenvironment-responsive nano-heterojunction for synergistic induction of cuproptosis and inhibition of colorectal cancer progression.Journal of nanobiotechnology · 2025Article
- Shikonin as a Dietary Phytochemical with Multi-Target Anti-Cancer Activities: From Molecular Mechanisms to Translational Applications.Nutrients · 2025Review
- Multi-omics analysis of parthanatos related molecular subgroup and prognostic model development in stomach adenocarcinoma.PloS one · 2025Article
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Authors and funding
21 authors.
Funding
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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