title: Autocrine prostaglandin E₂ signaling promotes promonocytic leukemia cell survival via COX-2 expression and MAPK pathway.
abstract: The COX-2/PGE₂ pathway has been implicated in the occurrence and progression of cancer. The underlying mechanisms facilitating the production of COX-2 and its mediator, PGE₂, in cancer survival remain unknown. Herein, we investigated PGE₂-induced COX-2 expression and signaling in HL-60 cells following menadione treatment. Treatment with PGE₂ activated anti-apoptotic proteins such as Bcl-2 and Bcl-xL while reducing pro-apoptotic proteins, thereby enhancing cell survival. PGE₂ 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 PGEv, and restored the menadione- induced cell death. In addition, pretreatment of cells with the MEK inhibitor PD98059 and the PKA inhibitor H89 abrogated the PGE₂-induced expression of COX-2, suggesting involvement of the MAPK and PKA pathways. These results demonstrate that PGE₂ signaling acts in an autocrine manner, and specific inhibition of PGE₂ will provide a novel approach for the treatment of leukemia.
authors: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Korea; Department of Biomedical Engineering and Sciences, School of Mechanical & Manufacturing Engineering, National University of Sciences & Technology, Islamabad, Pakistan.
authors: Adeeb
authors: A
authors: Shehzad
authors: Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 700-721, Korea.
authors: Jaetae
authors: J
authors: Lee
authors: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Korea.
authors: Young Sup
authors: YS
authors: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D034921:Lamin Type B / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D005419:Flavonoids; D007546:Isoquinolines; D034921:Lamin Type B; D034741:RNA, Small Interfering; D013449:Sulfonamides; D024483:Vitamin K 3; D051546:Cyclooxygenase 2; D011065:Poly(ADP-ribose) Polymerases; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D015232:Dinoprostone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D007213:Indomethacin