PXD059365-1

PXD059365 is an original dataset announced via ProteomeXchange.

Title	Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy
Description	Metabolic heterogeneity resulting from the intrinsic heterogeneity of human tumors has been shown to cause a myriad of adverse outcomes of tumor therapy, including resistance to chemotherapy, but the mechanisms inside remain largely unknown. Here, we found that the de novo pyrimidine synthesis pathway, which we previously identified as crucial for the proliferation of gastric and colon cancer cells, determines the chemosensitivity of these cancer types. In the chemosensitive cells, chemotherapeutic drugs such as 5-FU promoted the degradation of CAD, an enzyme that is rate-limiting for pyrimidine synthesis, leading to the apoptosis of these cells. We also found that CAD needed to be cleaved, by activated caspase-3 on its Asp1371 residue, before its degradation. Upregulation of CAD, either by overexpression or by a mutation on the Asp1371 to block the caspase-3 cleavage, conferred tumor chemoresistance in both mouse xenograft models and the Cldn18-ATK mouse gastric tumor models. Importantly, mutations related to Asp1371 of CAD were found in gastric tumor samples of patients who underwent unsuccessful neoadjuvant chemotherapy. By searching for a compound that is capable of degradating the CAD-Asp1371 mutant, we discovered that a compound called RMY-186 can be used to treat chemoresistant tumors related to CAD mutations, resulting in a significant improvement in the effectiveness of chemotherapy. We have, therefore, revealed the vulnerability of de novo pyrimidine synthesis during chemotherapy, which can be targeted to overcome chemotherapeutic resistance and augment the antitumor efficacy of genotoxic chemotherapy agents.
HostingRepository	iProX
AnnounceDate	2025-01-01
AnnouncementXML	Submission_2025-01-01_21:09:57.300.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jingsong Ma
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 240

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-01 21:09:42	ID requested
⏵ 1	2025-01-01 21:09:57	announced

Dataset with its publication pending

submitter keyword: Tumor heterogeneity

Pyrimidine metabolism

CAD

Caspase-3

Chemosensitivity

Xuehui Hong
contact affiliation	Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University
contact email	hongxu@xmu.edu.cn
lab head
Jingsong Ma
contact affiliation	Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University
contact email	majingsongWYY@126.com
dataset submitter

iProX dataset URI