Autocrine prostaglandin E(2) signaling promotes promonocytic leukemia cell survival via COX-2 expression and MAPK pathway

The COX-2/PGE(2) pathway has been implicated in the occurrence and progression of cancer. The underlying mechanisms facilitating the production of COX-2 and its mediator, PGE(2), in cancer survival remain unknown. Herein, we investigated PGE(2)-induced COX-2 expression and signaling in HL-60 cells following menadione treatment. Treatment with PGE(2) activated anti-apoptotic proteins such as Bcl-2 and Bcl-xL while reducing pro-apoptotic proteins, thereby enhancing cell survival. PGE(2) not only induced COX-2 expression, but also prevented casapse-3, PARP, and lamin B cleavage. Silencing and inhibition of COX-2 with siRNA transfection or treatment with indomethacin led to a pronounced reduction of the extracellular levels of PGE(2), and restored the menadione-induced cell death. In addition, pretreatment of cells with the MEK inhibitor PD98059 and the PKA inhibitor H89 abrogated the PGE(2)-induced expression of COX-2, suggesting involvement of the MAPK and PKA pathways. These results demonstrate that PGE(2) signaling acts in an autocrine manner, and specific inhibition of PGE(2) will provide a novel approach for the treatment of leukemia. [BMB Reports 2015; 48(2): 109-114]