Uterine corpus endometrial carcinoma is one of the most common female pelvic malignancies. Carfilzomib, a second-generation Proteasome Inhibitor (PI), is currently being used for the treatment of multiple myelomas by inhibiting the pathways of IRE1-XBP1 and PERK-eIf2α. However, when used to treat solid tumors, carfilzomib activated the XBP1-IRE1 pathway without affecting PERK-eIf2α. This study aimed to elucidate the function of carfilzomib in UCEC cells and to uncover the influence of PIs on specific cancer cells. Here, two cell lines were treated with carfilzomib, and cell viability, and protein and gene expressions were evaluated. In addition, tumor-carrying BALB/c immunodeficint mice were treated with carfilzomib with or without UMI-77 supplementation, and tumor growth was analyzed. We found that Carfilzomib treatment increased apoptosis and the expression of ER stress signaling markers and pro-apoptotic proteins (e.g., Noxa and Puma) increased, whereas the expression of anti-apoptotic proteins (e.g., Bcl-2 and Bcl-xl) decreased. The expression of markers related to three different ER stress pathways were affected by carfilzomib treatment. In nude mice models, carfilzomib function was more pronounced with UMI-77 supplementation. To conclude, we have shown that Carfilzomib triggers ER stress in UCEC cells in vitro and leads to tumor necrosis in vivo.
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