D-Cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Romain Hamelin  

LAB HEAD: Jean-Claude Martinou

PROVIDER: PXD063479 | Pride | 2025-09-01

REPOSITORIES: Pride