Carcinogenesis Advance Access published online on July 20, 2005
Carcinogenesis, doi:10.1093/carcin/bgi185
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1 Department of Food Science and Biotechnology, National Chung Hsing University, 250 Kuokuang Road, Taichung 40227, Taiwan
* To whom correspondence should be addressed. The molecular mechanism of sulforaphane on the induction of metallothioneins (MTs) genes in HepG2 cells and the antiproloferative effects of sulforaphane were investigated in this study. Treatment of the cells with sulforaphane at non-toxicity concentration (0-20 µM) resulted in coordinately increases the induction of MT-I and MT-II mRNA, following by corresponding increases in MT protein expression. Western blot analysis revealed the increased level of the transcription factor, Nrf2 in a time-dependent manner from sulforaphane-treated cells. Furthermore, sulforaphane activated the ERK, p38, and JNK mitogen-protein kinase pathways. SB203580, a specific inhibitor of p38 and PD98059, a specific inhibitor of ERK, abolished sulforaphane-induced MT protein expression, whereas SP600125, a specific inhibitor of JNK, had no significant effect. At relatively high concentration (30-100 µM), sulforaphane is a cell growth modulator, as it induced apoptotic cell death characterized by internucleosomal DNA fragmentation and caused a rapid induction of caspase-3 activity, according to the appearance of the caspase-3 fragments and stimulated proteolytic cleavage of poly (ADP-ribose) polymerase (PARP) in time-dependent. Moreover, sulforaphane-induced apoptotic cell death was accompanied by up-regulation of Bax and down-regulation of Bcl-2 and Bcl-XL protein. Sulforaphane-induced DNA fragmentation was blocked by the N-acetyl-L-cysteine and catalase, suggesting that the death signaling was triggered by oxidative stress. Taken together these results strongly suggest that at low concentrations of sulforaphane, activation of MAPKs such as ERK and p38 pathway lead to Nrf2-mediated metallothionein gene expression. Whereas at higher concentration of sulforaphane, sulforaphane is an effective apoptosis inducer in HepG2 cells through regulation of Bcl-2 family molecular and activation of ICE/Ced-3 protease (caspase-3) cascade. The results from this study may provide more evidence for its chemopreventive function.
Received April 29, 2005
Revised July 4, 2005
Accepted July 12, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Effect of sulforaphane on metallothionein expression and induction of apoptosis in human hepatoma HepG2 cells
Gow-Chin Yen, E-mail: gcyen{at}nchu.edu.tw
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