Copper induces cystine/glutamate antiporter SLC7A11 through the activation of Nrf2 and Atox1 pathways.

Amino acid metabolism plays a crucial role in tumor biology. The sodium-independent cystine/glutamate exchange system, known as system Xc-, is significantly activated in cancer cells and plays a role in tumor progression. Copper (Cu), an essential micronutrient, plays a crucial role in physiological processes; however, its accumulation in tumors has been associated with tumor progression. Nonetheless, the relationship between system Xc--mediated amino acid metabolism and Cu remains inadequately understood. In this study, CuCl2 treatment resulted in the significant induction of SLC7A11, a light chain subunit of system Xc-, and glutamate receptor mGluR1 expression in human triple-negative MDA-MB-231 cells. Conversely, FeCl2 treatment induced the expression of SLC7A11 but not mGluR1, indicating that Cu specifically activated SLC7A11-mediated amino acid metabolism. The investigation focused on the role of Nrf2, a redox-sensitive transcription factor, in the induction of SLC7A11 under conditions of oxidative stress induced by CuCl2 treatment. Upon treatment with CuCl2, the nuclear translocation of Nrf2 was observed, and knockdown of Nrf2 significantly suppressed the induction of SLC7A11. Given that the Cu chaperone, antioxidant-1 (Atox1), functions as a Cu-dependent transcription factor, the role of Atox1 in the expression of SLC7A11 was further investigated. Like the effects of Nrf2 knockdown, Atox1 was found to play a pivotal role in the Cu-mediated induction of SLC7A11. Our findings indicate that intratumoral Cu influences the expression of SLC7A11 and may play a role in tumor progression.