Divergent effects of copper and cisplatin on the endocytic trafficking of copper transporter-1.

Cisplatin (CDDP), a widely used chemotherapeutic agent, enters mammalian cells through high-affinity copper transporter CTR1. We found that copper preloading reduces CDDP cytotoxicity, supporting a shared uptake mechanism for copper and cisplatin. CDDP-induced CTR1 endocytosis requires both the amino-terminal His-Met motifs and the conserved 150MXXM154 pore-motif, similar to copper-mediated transport. Following internalization, CTR1 is routed through VPS35-positive endosomes and ultimately targeted to lysosomes. However, unlike copper, CDDP suppresses local recycling of CTR1 to plasma membrane and delays its lysosomal delivery. While copper promotes rapid lysosomal clearance of CTR1, CDDP results in prolonged intracellular trafficking. Additionally, CDDP enhances lysosomal size and cathepsin activity, indicating lysosomal activation. These findings reveal distinct mechanisms underlying CTR1-mediated cisplatin uptake and its impact on lysosomal physiology.