SLC7A11/xCT-mediated Cystine Uptake Regulates Intracellular Glutathione and Promotes Antioxidant Defense in Lymphatic Endothelial Cells

Background/aim: In a tongue-submandibular lymph node (SLN) metastasis model, the cystine/glutamate transporter solute carrier family 7, member 11 (Slc7a11), also known as xCT, was found to increase in lymphatic endothelial cells (LECs) within SLNs prior to melanoma cell metastasis. However, the precise mechanism by which xCT influences LECs remains unclear. This study aimed to explore the role of xCT in primary cultured LECs.

Materials and methods: To determine whether xCT is involved in cystine uptake and glutathione (GSH) synthesis in primary cultured LECs, cystine uptake and GSH assays were conducted. The antioxidant role of xCT was evaluated by measuring intracellular reactive oxygen species (ROS). Additionally, xCT expression was analyzed in human melanoma metastatic lymph nodes using immunohistochemical staining.

Results: Slc7a11-knockdown LECs exhibited significantly reduced cystine uptake and intracellular GSH levels. ROS levels in Slc7a11-knockdown LECs were found to be increased compared to those in control LECs under H₂O₂-induced oxidative stress conditions. xCT stability is regulated by CD44v; therefore, we evaluated whether LYVE-1, a hyaluronic acid receptor in LECs, regulates xCT expression. LYVE-1 upregulates Slc7a11 mRNA expression, increasing GSH production in LECs. Furthermore, xCT expression was observed in LECs within human melanoma metastatic lymph nodes.

Conclusion: xCT functions as a cystine transporter, contributing to increased GSH levels in lymphatic fluid in melanoma metastasis.