Induction of apoptosis by esculetin in human leukemia U937 cells through activation of JNK and ERK
- Division of Biological Sciences, College of Natural Science, Pusan National University, Busan 609-735 (Korea, Republic of)
- Faculty of Applied Marine Science, Cheju National University, Jeju Special Self-Governing Province 690-756 (Korea, Republic of)
- Department of Microbiology, College of Medicine and Center for Viral Disease Research, Inje University, Busan 614-735 (Korea, Republic of)
- Department of Immunology, School of Medicine, Keimyung University, Taegu 700-712 (Korea, Republic of)
- Department of Anatomy, Graduate School of Oriental Medicine, Pusan National University, 609-735 (Korea, Republic of)
- Department of Chemistry, Hanyang University, Seoul 133-791 (Korea, Republic of)
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.
- OSTI ID:
- 21077936
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 227, Issue 2; Other Information: DOI: 10.1016/j.taap.2007.10.003; PII: S0041-008X(07)00446-2; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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