Induction of CDK inhibitors (p21WAF1 and p27Kip1) and bak in the β-lapachone-induced apoptosis of human prostate cancer cells

被引:45
作者
Don, MJ
Chang, YH
Chen, KK
Ho, LK
Chau, YP
机构
[1] Natl Yang Ming Univ, Sch Life Sci, Inst Anat & Cell Biol, Taipei 112, Taiwan
[2] Taipei Vet Gen Hosp, Dept Surg, Div Urol, Taipei, Taiwan
[3] Natl Res Inst Chinese Med, Taipei, Taiwan
[4] Natl Yang Ming Univ, Sch Med, Dept Urol, Taipei, Taiwan
[5] Natl Yang Ming Univ, Sch Med, Dept Pharmacol, Taipei, Taiwan
关键词
D O I
10.1124/mol.59.4.784
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
beta -Lapachone, a novel anti-neoplastic drug, induces various cancer cells to undergo apoptosis. In a previous report, we showed that beta -lapachone-induced apoptosis of HL-60 cells is mediated by oxidative stress. However, in the present study, we found that beta -lapachone-induced apoptosis of human prostate cancer (HPC) cells may be independent of oxidative stress. In contrast to the 10-fold beta -lapachone-induced increase in H2O2 production seen in HL-60 cells, only a 2- to 4-fold increase was observed in HPC cells. N-acetyl-L-cysteine (NAC), a thiol antioxidant, inhibited the apoptosis in DU145 cells after 12 h exposure to beta -lapachone. Nonetheless, NAC, along with other antioxidants, failed to exert similar effect in HPC cells subjected to beta -lapachone treatment for 24 h. Under this premise, we suggest that the oxidative stress may not play a crucial role in beta -lapachone-mediated HPC cell apoptosis. Here we demonstrate that damage to genomic DNA is the trigger for the apoptosis of HPC cells induced by beta -lapachone. According to our results, beta -lapachone stimulates DNA dependent kinase expression and poly(ADP-ribose) polymerase cleavage in advance of significant morphological changes. beta -Lapachone promotes the expression of cyclin-dependent kinase (cdk) inhibitors (p21(WAF1) and p27(Kip1)), induces bak expression, and subsequently stimulates the activation of caspase-7 but not of caspase-3 or caspase-8 during the apoptosis of HPC cells. Taken together, these results suggest that the signaling pathway involving the beta -lapachone-induced apoptosis of HPC cell may be by DNA damage, induction of cdk inhibitors (p21 and p27), and then subsequent stimulation of caspase-7 activation.
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收藏
页码:784 / 794
页数:11
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