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KMID : 1140120090140010040
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Cancer Prevention Research
2009 Volume.14 No. 1 p.40 ~ p.47
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Involvement of Extracellular-Regulated Kinase in Esculetin-Induced Apoptosis of Bcl-2 Overexpressing Human Leukemia U937 Cells
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Park Cheol
Kwon Hyun-Ju
Choi Byung-Tae
Hwang Hye-Jin
Kim Byung-Woo
Choi Yung-Hyun
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Abstract
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Bcl-2 is the prototypic anti-apoptotic protein involved in the regulation of apoptosis. Commonly, overexpression of Bcl-2 confers resistance to the apoptotic effect of chemo- and radiotherapy. Esculetin is a coumarin 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 observed overexpressing Bcl-2 attenuated esculetin-induced up-regulation of death receptor 4 (DR4), down-regulation of X-linked inhibitor of apoptosis protein (XIAP) and β-catenin, and degradation of DNA fragmentation factor 45/inhibitor of caspase-activated DNase (DFF45/ICAD). However, HA14-1, a small molecule Bcl-2 antagonist, increased sensitivity to the apoptotic effect of the esculetin in Bcl-2 overexpressing U937/Bcl-2 cells that correlated with the loss of mitochondrial membrane potential (MMP). Furthermore, inactivation of extracellular-regulated kinase (ERK) by PD98059 significantly decreased esculetin-induced cell death and restored XIAP, β-catenin, phospholipase Cγ-1 (PLCγ1) and DFF45/ICAD in pretreatment with HA14-1 in Bcl-2 overexpressing U937/Bcl-2 cells. These results demonstrate an additional mechanism of regulation of cell survival mediated by Bcl-2, namely through ERK. Therefore, directed inhibition of Bcl-2 may alter diverse pathways controlling cell survival and overcome the apoptotic resistance that is the hallmark of human leukemia cells.
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KEYWORD
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Esculetin, Apoptosis, Bcl-2, ERK
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