PXD063479

PXD063479 is an original dataset announced via ProteomeXchange.

Title	D-Cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1
Description	Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, a transport system that imports L-cystine to strengthen antioxidant defenses, thereby promoting tumour survival and progression. We have exploited this feature of cancer cells by transforming xCT/CD98 overexpression into a selective vulnerability. We observed that the D-enantiomer of cysteine (D-Cys), unlike other D-amino acids, selectively impaired the proliferation of xCT/CD98-overexpressing cancer cell lines, particularly under high oxygen concentrations. D-Cys acquired by xCT/CD98 specifically inhibited the cysteine desulfurase NFS1, the sulfur donor of cellular iron-sulfur protein biogenesis3. NFS1 was still able to form the D-Cys-ketimine intermediate of pyridoxal phosphate, but steric constraints prevented the enzyme to transfer the D-Cys-ketimine sulfur to its active-site Cys381 residue, causing enzymatic inactivation. This defect compromised all cellular Fe-S cluster-dependent functions, including mitochondrial respiration, nucleotide metabolism, and maintenance of genome integrity, leading to decreased oxygen consumption, DNA damage, and cell cycle arrest. In vivo D-Cys administration diminished tumour growth of human triple-negative breast cancer cells implanted orthotopically into the mouse mammary gland. Hence, D-Cys could represent a simple therapy to selectively target those forms of cancer characterized by overexpression of xCT/CD98.
HostingRepository	PRIDE
AnnounceDate	2025-09-01
AnnouncementXML	Submission_2025-08-31_17:01:42.987.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Romain Hamelin
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-30 00:56:01	ID requested
⏵ 1	2025-08-31 17:01:43	announced

Zangari J, Stehling O, Freibert SA, Bhattacharya K, Rouaud F, Serre-Beinier V, Maundrell K, Montessuit S, Ferre SM, Vartholomaiou E, Schulz V, Zuhra K, Gonz, á, lez-Ruiz V, Hanschke S, Tsukamoto T, Cerezo M, Szabo C, Rudaz S, Boniecki MT, Cygler M, Lill R, Martinou JC, D-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1. Nat Metab, 7(8):1646-1662(2025) [pubmed]

10.1038/s42255-025-01339-1;

submitter keyword: iron-sulfur cluster, iron-sulfur protein biogenesis, iron homeostasis.,Cancer, amino acid

Jean-Claude Martinou
contact affiliation	Department of Molecular and Cellular Biology, Faculty of Sciences, University of Geneva, 30 quai Ernest Ansermet, Geneva, Switzerland
contact email	jean-claude.martinou@unige.ch
lab head
Romain Hamelin
contact affiliation	PCF
contact email	romain.hamelin@epfl.ch
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/09/PXD063479

PRIDE project URI

• PRIDE
  1. PXD063479
     1. Label: PRIDE project
     2. Name: D-Cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1