The Role of CD44v9/xCT as a Protective Mechanism Against ROS-Induced Chemotherapy in Gastric Cancer

Gastric cancer remains a public health concern all over the world and specifically in South America and Eastern Asia. The 5-year survival rate for GC remains dismal and this could be attributed to diagnosis at a late stage. The GC tumor has been observed to possess a unique subpopulation of cells known as cancer stem cells (CSCs). Furthermore, these stem cells have been shown to be identified through a marker known as cluster-of-differentiation 44 (CD44). It has been reported that CD44+ cells possess a higher ability for defense against reactive oxygen species (ROS) and this has been attributed to its role in stabilizing xCT on the surface of the cancer stem cells (CSCs). The goal of our work was to utilize an in vitro and in vivo model to identify the role of the CD44v9-xCT mechanism and how it may be contributing to resistance through defense against ROS. Overall, our work showed that when CD44+ xCT knockdown MSI-H IM95 cells were treated with optimal dose of sulfasalazine alongside varying concentrations of cisplatin, they were sensitized to the treatment. This was also visualized in the patient-derived gastric cancer organoid model, which inhibited the xCT transporter with sulfasalazine treatment. In conclusion, our findings indicate that CD44 stabilized xCT transporter on CSCs is contributing to ROS defense and is allowing for persistence of the tumor. Furthermore, our findings elucidate that CD44-xCT system may be a potential therapeutic target to allow for sensitization to treatment