Autocrine prostaglandin E2 signaling promotes promonocytic leukemia cell survival via COX-2 expression and MAPK pathway
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The COX-2/PGE2 pathway has been implicated in the occurrenceand progression of cancer. The underlying mechanismsfacilitating the production of COX-2 and its mediator,PGE2, in cancer survival remain unknown. Herein, weinvestigated PGE2-induced COX-2 expression and signaling inHL-60 cells following menadione treatment. Treatment withPGE2 activated anti-apoptotic proteins such as Bcl-2 and Bcl-xLwhile reducing pro-apoptotic proteins, thereby enhancing cellsurvival. PGE2 not only induced COX-2 expression, but alsoprevented casapse-3, PARP, and lamin B cleavage. Silencingand inhibition of COX-2 with siRNA transfection or treatmentwith indomethacin led to a pronounced reduction of theextracellular levels of PGE2, and restored the menadione-induced cell death. In addition, pretreatment of cells withthe MEK inhibitor PD98059 and the PKA inhibitor H89abrogated the PGE2-induced expression of COX-2, suggestinginvolvement of the MAPK and PKA pathways. These resultsdemonstrate that PGE2 signaling acts in an autocrine manner,and specific inhibition of PGE2 will provide a novel approachfor the treatment of leukemia.
Abstract
The COX-2/PGE2 pathway has been implicated in the occurrenceand progression of cancer. The underlying mechanismsfacilitating the production of COX-2 and its mediator,PGE2, in cancer survival remain unknown. Herein, weinvestigated PGE2-induced COX-2 expression and signaling inHL-60 cells following menadione treatment. Treatment withPGE2 activated anti-apoptotic proteins such as Bcl-2 and Bcl-xLwhile reducing pro-apoptotic proteins, thereby enhancing cellsurvival. PGE2 not only induced COX-2 expression, but alsoprevented casapse-3, PARP, and lamin B cleavage. Silencingand inhibition of COX-2 with siRNA transfection or treatmentwith indomethacin led to a pronounced reduction of theextracellular levels of PGE2, and restored the menadione-induced cell death. In addition, pretreatment of cells withthe MEK inhibitor PD98059 and the PKA inhibitor H89abrogated the PGE2-induced expression of COX-2, suggestinginvolvement of the MAPK and PKA pathways. These resultsdemonstrate that PGE2 signaling acts in an autocrine manner,and specific inhibition of PGE2 will provide a novel approachfor the treatment of leukemia.
참고문헌 (21)
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