Resumen
The xCT transporter of oxidized form of cysteine has been recognized as fundamental for cellular amino acid and redox homeostasis. Increasing number of data suggests that xCT inhibition-induced ferroptosis has great potential for development of novel anti-cancer therapeutics for pancreatic cancer patients. The aim of this study was to investigate potential resistance mechanisms that cancer cells with genetically disrupted xCT (xCTKO) may exploit in order to develop resistance to ferroptosis. Our data clearly showed that shuttle of reduced cysteine between cancer xCTKO and neighboring cells provide protection of the former. Importantly, this shuttle seems to be fueled by the import and reduction of oxidized cysteine by xCT-proficient feeder layer. In summary, two important findings are: (1) supply of the reduced cysteine has to be taken in consideration when xCT-based ferroptosis inducers are used, and (2) systemic inhibition of xCT could be potential approach in overcoming this resistant mechanism.