MK886-induced apoptosis depends on the 5-LO expression level in human malignant glioma cells.
Mounting evidence suggests that lipoxygenase (LO)-catalyzed products may play a key role in the development and progression of human cancers. In this study, we analyzed the effects of a 5-LO inhibitor, which inhibits the conversion of arachidonic acid to leukotrienes, on cell proliferation and apoptosis in human malignant glioma cells, including 5-LO-expressing cells U-87MG, A172 and 5-LO non-expressing cell U373. Growth of U-87MG and A172 cells, but not that of U373 cells, was inhibited in a dose-dependent manner by treatment with MK886. Similarly, specific 5-LO silencing by small interfering RNA reduced the growth of U-87MG and A172 cells. MK886 treatment reduced 5-LO activity independently of 5-LO-activating protein (FLAP) in human malignant glioma cells. MK886 treatment also induced cell apoptosis, measured by DNA fragmentation and nuclear condensation, in U-87MG and A172 cells but there were no signs in U373 cells. Moreover, this treatment reduced ERKs phosphorylation and anti-apoptotic molecule Bcl-2 expression, and increased Bax expression in U-87MG and A172 cells. In summary, our results show there is a link between the 5-LO expression status and the extent of MK886-inhibited cell proliferation and apoptosis. Taken together, this study suggest that 5-LO is a possible target for treating patients with gliomas, and 5-LO inhibition might be potent therapy for patients with 5-LO-expressing malignant gliomas.
Lim
Jung Yeon
JY
Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Oh
Ji Hyeon
JH
Jung
Ju Ri
JR
Kim
Seong Muk
SM
Ryu
Chung Hun
CH
Kim
Hong-Tae
HT
Jeun
Sin-Soo
SS
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D002722:Chlorobenzenes
D051017:Apoptosis Regulatory Proteins; D001094:Arachidonate 5-Lipoxygenase; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C060893:MK-886; D002722:Chlorobenzenes