Oncogenic role of the SLC7A13-SLC3A1 cystine transporter in human luminal breast cancer and its cryo-EM structure

Cancer cells often uptake more cystines to increase glutathione (GSH) biosynthesis and reduce reactive oxygen species (ROS) and ROS-induced ferroptosis. However, few molecules of these processes are targetable for cancer therapy. The gene for SLC7A13, which forms a cystine transporter with SLC3A1, was amplified in 19.7% and overexpressed in 49.7% of breast cancers, associated with worse prognosis in luminal tumors. SLC7A13 overexpression promoted cell survival or proliferation, while SLC7A13 silencing reduced cystine uptake and GSH biosynthesis and increased lipid ROS levels. The human SLC7A13-SLC3A1 complex’s structure was solved by Cryo-EM at 2.6Å resolution as a heterodimeric dimer, consistent with another SLC3A1 transporter. The complex had a specific pocket with unique residues for regulating substrate uptake. These findings provide a novel therapeutic opportunity for cancer treatment.