title: Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation.
abstract: Withaferin A, a major chemical constituent of Withania somnifera, has been reported for its tumor cell growth inhibitory activity, antitumor effects, and impairing metastasis and angiogenesis. The mechanism by which withaferin A initiates apoptosis remains poorly understood. In the present report, we investigated the effect of withaferin A on the apoptotic pathway in U937 human promonocytic cells. We show that withaferin A induces apoptosis in association with the activation of caspase-3. JNK and Akt signal pathways play crucial roles in withaferin A-induced apoptosis in U937 cells. Furthermore, we have shown that overexpression of Bcl-2 and active Akt (myr-Akt) in U937 cells inhibited the induction of apoptosis, activation of caspase-3, and PLC-gamma1 cleavage by withaferin A. Taken together, our results indicated that the JNK and Akt pathways and inhibition of NF-kappaB activity were key regulators of apoptosis in response to withaferin A in human leukemia U937 cells.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea.
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Oh
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Lee
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Sang Han
authors.initials: SH
authors.lastname: Lee
authors.forename: Jin Man
authors.initials: JM
authors.lastname: Lee
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: Jong-Wook
authors.initials: JW
authors.lastname: Park
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000378:metabolism; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D007938:Leukemia / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D054358:Withanolides
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D054358:Withanolides; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D020782:Matrix Metalloproteinases; C009684:withaferin A; D004875:Ergosterol