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Journal of Cancer Prevention

Original Article

Cancer prevention research 2007; 12(4): 246-254

Published online December 30, 2007

© Korean Society of Cancer Prevention

Sulforaphane-induced Apoptosis is Regulated by Bcl-2 and Caspase-3 in Human Leukemia U937 Cells through Modulation of the ERK and Akt Pathways

Cheng-Yun Jin1, Dong-Oh Moon2, Yung Hyun Choi3, Cheol Park3, Mun-Ock Kim3, Jae-Dong Lee1, Tae-Ho Lee1 and Gi-Young Kim2


Sulforaphane (SFN) is a major isothiocyanate compound shown to induce anti-proliferation and apoptosis in solid human cancer cell lines. However, the mechanisms responsible for SFN-induced apoptosis are poorly understood in leukemia cells. In the present study, we first investigated the role of the anti-apoptotic protein, Bcl-2, in response to SFN-mediated apoptosis in human leukemia U937 cells. We also investigated whether SFN-induced apoptosis involved mitogen-activated protein kinases (MAPKs) and the Akt pathway. Treatment with 4ՌM SFN for 48 h resulted in a significant induction of apoptosis in U937 cells. This effect was characterized by accumulation of cells with sub-G1 phase DNA content, caspase activation, and poly (ADP-ribose) polymerase (PARP) degradation. In contrast, U937/Bcl-2 exposed to the same SFN treatment only exhibited a slight induction of apoptotic features. A specific Bcl-2 inhibitor, HA14-1, significantly increased SFN-induced apoptosis with caspase-3 activation. SFN treatment also increased extracellular-signal regulating kinase (ERK) phosphorylation in U937 cells, and combined treatment with a specific ERK inhibitor (PD98059) and SFN appeared to significantly inhibit SFN-induced apoptosis by interfering with caspase-3 activation. In contrast, treatment with SFN decreased the phosphorylation of Akt, which resulted in significant induction of apoptosis and combined treatment with Akt upstream inhibitor LY294002 induced more potent apoptosis. These results indicate that SFN-induced apoptosis is regulated by Bcl-2 and caspase in human leukemic U937 cells through modulation of the ERK and Akt pathways. (Cancer Prev Res 12, 246-255, 2007)

Keywords: Sulforaphane, Bcl-2, Caspase-3, Mitogen-activated protein kinase

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