EP4 influences bortezomib resistance in multiple myeloma by modulating endoplasmic reticulum stress via the phosphatidylinositol 3-kinase/protein kinase B pathway.

Multiple myeloma, a hematologic malignancy characterized by the uncontrolled proliferation of plasma cells, presents a significant therapeutic challenge, particularly due to the development of resistance to bortezomib, a cornerstone in its treatment. The prostaglandin E receptor 4 (PTGER4 or EP4), a component of the prostaglandin E2 signaling pathway, has emerged as a potential modulator of drug resistance. However, its precise mechanistic role in multiple myeloma remains inadequately understood. This study aims to elucidate the role of EP4 in bortezomib resistance, specifically focusing on its interaction with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. We employed a comprehensive approach that integrates bioinformatics analysis of multiple myeloma-related genes from public databases with advanced molecular biology techniques. Our investigation examined EP4 expression in both bortezomib-resistant and bortezomib-sensitive multiple myeloma cell lines. The impacts of EP4 overexpression on various cellular processes, including proliferation, apoptosis, endoplasmic reticulum (ER) stress, and bortezomib sensitivity, were examined. Both in vitro and in vivo experiments were conducted to delineate the role of EP4 in modulating the PI3K/AKT pathway and its downstream effects on drug resistance. Our findings revealed a significant decrease in EP4 expression in multiple myeloma tissues, with important implications for patient survival and prognosis. Overexpression of EP4 in bortezomib-resistant cell lines enhanced their sensitivity to the drug, inhibited cell growth, and induced apoptosis. These effects were accompanied by decreased phosphorylation of PI3K and AKT, along with increased expression of glucose-regulated protein 78 000, an indicator of ER stress. Notably, these effects were partially reversed when combined with treatment using an AKT agonist. EP4 plays a significant role in modulating bortezomib resistance in multiple myeloma through its effects on the PI3K/AKT pathway and ER stress. These findings underscore the therapeutic potential of targeting EP4 to enhance bortezomib efficacy and improve clinical outcomes for patients with multiple myeloma.