MK886 inhibits the proliferation of HL-60 leukemia cells by suppressing the expression of mPGES-1 and reducing prostaglandin E2 synthesis.
Microsomal prostaglandin E synthase-1 (mPGES-1), an inducible enzyme that specifically catalyzes the conversion of prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2), has been reported to be over-expressed in a variety of solid tumor cells and tissues, but not in normal tissues. Its association with leukemia, however, has not been fully investigated. Our study revealed, for the first time, that mPGES-1 is over-expressed in human acute myeloid leukemia HL-60 cells. Cytotoxicity assays and flow cytometry showed that MK886, an inhibitor of mPGES-1, inhibits proliferation of HL-60 cells and induces apoptosis in a dose- and time-dependent manner, which may result from down-regulation of mPGES-1 expression and PGE2 synthesis. Evaluation of mediators of apoptotic signaling revealed up-regulation of BAX expression and caspase-3 activity, as well as significant decreases in Bcl2 and P-Akt. We conclude that MK886 reduces the viability of leukemia HL-60 cells by reducing mPGES-1 expression and PGE2 synthesis in a dose-dependent manner, which strongly suggests that mPGES-1 inhibitors should be considered as promising candidates for leukemia treatment.
Department of Hematology, Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, The SUN Yat-sen Memorial Hospital of SUN Yat-sen University, 107 Yanjiangxi Rd, Guangzhou, People's Republic of China.
YiQing
Y
Li
SongMei
S
Yin
DaNian
D
Nie
ShuangFeng
S
Xie
LiPing
L
Ma
XiuJu
X
Wang
YuDan
Y
Wu
Jie
J
Xiao
D049109:Cell Proliferation / Q000187:drug effects*; D003864:Depression, Chemical; D015232:Dinoprostone / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D000071876:Prostaglandin-E Synthases; D013997:Time Factors; D014407:Tumor Cells, Cultured; D002722:Chlorobenzenes
D015232:Dinoprostone; D007211:Indoles; D019746:Intramolecular Oxidoreductases; D016859:Lipoxygenase Inhibitors; D000071876:Prostaglandin-E Synthases; C060893:MK-886; D002722:Chlorobenzenes; C000605862:PTGES protein, human