d-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1
Joséphine Zangari, Oliver Stehling, Sven‐Andreas Freibert, Kaushik Bhattacharya, Florian Rouaud, Véronique Serre‐Beinier, Kinsey Maundrell, Sylvie Montessuit, Sabrina Ferré, Evangelia Vartholomaiou, Vinzent Schulz, Karim Zuhra, Víctor González‐Ruiz, Sahra Hanschke, Takashi Tsukamoto, Michaël Cerezo, Csaba Szabó, Serge Rudaz, Michal T. Boniecki, Mirosław Cygler, Roland Lill, Jean‐Claude Martinou
Abstract
Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, an L-cystine transport system that strengthens antioxidant defences, thereby promoting tumour survival and progression. Here, we show that the D-enantiomer of cysteine (D-Cys) is selectively imported into xCT/CD98-overexpressing cancer cell lines and impairs their proliferation, particularly under high oxygen concentrations. Intracellular D-Cys specifically inhibits the mitochondrial cysteine desulfurase NFS1, a key enzyme of cellular iron-sulfur protein biogenesis, by blocking sulfur mobilization due to steric constraints. NFS1 inhibition by D-Cys affects all cellular iron-sulfur cluster-dependent functions, including mitochondrial respiration, nucleotide metabolism and maintenance of genome integrity, leading to decreased oxygen consumption, DNA damage and cell cycle arrest. D-Cys administration diminishes 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.