Role of the MUC1‐C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma

Mucin 1 C‐terminal subunit (MUC1‐C) has been introduced as a key regulator for acquiring drug resistance in various cancers, but the functional role of MUC1‐C in urothelial carcinoma (UC) cells remains unknown. We aimed to elucidate the molecular mechanisms underlying the acquisition of cisplatin (CDDP) resistance through MUC1‐C oncoprotein in UC cells. MUC1‐C expression was examined immunohistochemically in tumor specimens of 159 UC patients who received CDDP‐based perioperative chemotherapy. As a result, moderate to high MUC1‐C expression was independently associated with poor survival in UC patients. Using human bladder cancer cell lines and CDDP‐resistant (CR) cell lines, we compared the expression levels of MUC1‐C, multiple drug resistance 1 (MDR1), the PI3K‐AKT‐mTOR pathway, and x‐cystine/glutamate transporter (xCT) to elucidate the biological mechanisms contributing to the acquisition of chemoresistance. MUC1‐C was strongly expressed in CR cell lines, followed with MDR1 expression via activation of the PI3K‐AKT‐mTOR pathway. MUC1‐C also stabilized the expression of xCT, which enhanced antioxidant defenses by increasing intracellular glutathione (GSH) levels. MUC1 down‐regulation showed MDR1 inhibition along with PI3K‐AKT‐mTOR pathway suppression. Moreover, it inhibited xCT stabilization and resulted in significant decreases in intracellular GSH levels and increased reactive oxygen species (ROS) generation. The MUC1‐C inhibitor restored sensitivity to CDDP in CR cells and UC murine xenograft models. In conclusion, we found that MUC1‐C plays a pivotal role in the acquisition of CDDP resistance in UC cells, and therefore the combined treatment of CDDP with a MUC1‐C inhibitor may become a novel therapeutic option in CR UC patients. Our present study demonstrated that mucin 1 C‐terminal peptide (MUC1‐C) plays a pivotal role in the acquisition of cisplatin (CDDP) resistance via multiple drug resistance 1 regulation and x‐cystine/glutamate transporter stabilization in urothelial cancer cells. The combined treatment of CDDP with a MUC1‐C inhibitor, GO‐203, may become a novel therapeutic option in CDDP‐resistant UC patients.