title: Induction of apoptosis by esculetin in human leukemia U937 cells through activation of JNK and ERK.
abstract: Esculetin is a phenolic compound that is found in various natural plant products and induces apoptosis in several types of human cancer cells. However, the underlying mechanisms of its action are not completely understood. In the present study, we used human leukemia cells to gain further insight into the mechanism of esculetin-induced anti-proliferative action and apoptosis. It was found that esculetin inhibits cell viability by inducing apoptosis, as evidenced by the formation of apoptotic bodies, DNA fragmentation, and the accumulation of cells in the sub-G1 phase. Esculetin-induced apoptosis was correlated with mitochondrial dysfunction, leading to the release of cytochrome c from the mitochondria to the cytosol, as well as the proteolytic activation of caspases. The z-DEVD-fmk caspase-3 inhibitor and the ectopic expression of anti-apoptotic Bcl-2 significantly inhibited esculetin-induced apoptosis, demonstrating the important role of caspase-3 and mitochondrial proteins in the observed cytotoxic effect. Furthermore, esculetin selectively increased the phosphorylation of extracellular-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not that of other kinases such as Akt and p38 activation. In addition, an ERK-specific inhibitor, PD98059, and a JNK-specific inhibitor, SP600125, showed inhibited sub-G1 phase DNA content, DNA fragmentation, caspase activation, and mitochondrial dysfunction induced by esculetin treatment. These results indicated that the JNK and ERK pathways were key regulators of apoptosis in response to esculetin in human leukemia U937 cells.
authors.affiliation: Division of Biological Sciences, College of Natural Science, Pusan National University, Busan 609-735, South Korea.
authors.forename: Cheol
authors.initials: C
authors.lastname: Park
authors.forename: Cheng-Yun
authors.initials: CY
authors.lastname: Jin
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Il-Whan
authors.initials: IW
authors.lastname: Choi
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Byung Tae
authors.initials: BT
authors.lastname: Choi
authors.forename: Su Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Won Ho
authors.initials: WH
authors.lastname: Lee
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D007202:Indicators and Reagents; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000378:metabolism; D020298:U937 Cells; D014468:Umbelliferones / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D061945:Caspase Inhibitors; D007202:Indicators and Reagents; D009842:Oligopeptides; D014468:Umbelliferones; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D045304:Cytochromes c; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D051966:Phospholipase C gamma; D020782:Matrix Metalloproteinases; C007628:esculetin