D-cysteine inhibits iron-sulfur cluster assembly and impairs tumour growth

Abstract Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98 to increase the import of L-cystine for antioxidant defense, thus supporting tumour cell survival and progression1,2. We have exploited this feature of cancer cells by transforming xCT/CD98 overexpression into a selective vulnerability. We found that the D-enantiomer of cysteine (Cys), but not other D-amino acids, impaired proliferation of numerous xCT/CD98-expressing cancer cell lines, whereas xCT/CD98-non-overexpressing (cancer) cells were unaffected. D-Cys acquired by xCT/CD98 specifically inhibited the cysteine desulfurase NFS1, the sulfur donor of cellular iron-sulfur protein biogenesis3. NFS1 was able to form the D-Cys-ketimine intermediate, but, due to steric incompatibility, failed to transfer the D-Cys sulfur to its active-site Cys381 residue, thereby blocking enzymatic activity. This led to a general defect of all cellular processes relying on iron-sulfur proteins, including mitochondrial respiration, nucleotide metabolism, and nuclear genome maintenance, resulting in reduced oxygen consumption, accumulation of 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.