Chemo-sensitizing effects of EP4 receptor-inducedinactivation of nuclear factor-$▫kappaB▫$
Gobec, Martina, farmacevtka, 1983- ...
The EP4 receptor conveys growth-inhibitory effects in mature and immature B cells via NF-kB. Herein, the EP4 receptor was evaluated as a potential therapeutic target for leukemia and lymphoma, whose ...survival depends on the constitutive activity of NF-ŽB. Utilizing a pharmacological approach, we proved that the EP4 receptor induces caspase-mediated apoptosis in malignantly transformed B cells, with the most prominent effect being on Burkitt's lymphoma cells. Since the increased activation of NF-kB underlies multi-drug resistance phenomena, we modulated this signaling pathway via EP4 receptor triggering. Pge1-OH, a specific EP4 receptor agonist, led to decreased NF-kB activity and a consequent decrease in levels of the antiapoptotic gene Bcl-xL in Ramos cells, resulting in an elevated sensitivity of cells towards bortezomib- and doxorubicin-induced chemotherapeutic effects. Our study identifies the as yet unrecognized potential of EP4 receptor agonists as chemo-sensitizing agents in B-cell lymphoma. The specific downregulation of NF-kB-dependent pathways in B-cell malignancies opens new possibilities for treatment and current therapy optimization using specific EP4 receptor agonists.
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