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 X_c^-, 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 X_c^--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 X_c^-, 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.