Department of Microbiology, and Center for Advanced Medical Education by BK21 Project, College of Medicine, Inha University, Incheon 400-712, Korea.
Exp Mol Med. 2010 May 31;42(5):327-34. doi: 10.3858/emm.2010.42.5.034.
Anticancer effects of beta-lapachone (beta-lap) are due to generation of ROS and metabolic catastrophes as a result of NAD(P)H:quinone oxidoreductase (NQO1)-mediated futile cycling between the oxidized and reduced forms of beta-lap. It has been shown that NQO1 is also essential for the TNF-induced activation of NF-kappaB and that beta-lap suppresses the TNF-induced NF-kappaB activation. We investigated whether or not NQO1 is involved and beta-lap suppresses the radiation-induced NF-kappaB activation using A549 human lung cancer cells and NQO1-knock down A549 cells (shNQO1 A549 cells). Irradiation with 4 Gy markedly increased the DNA binding activity of NF-kappaB in A549 cells, but not in the shNQO1 A549 cells, thus demonstrating that NQO1 plays a pivotal role in irradiation-induced NF-kappaB activation. Treatment with 10 micronM beta-lap for 4 h almost completely abrogated the radiation-induced increase in NF-kappaB activation and the transcription of NF-kappaB target genes such as bcl2, gadd45beta and cyclinD1. Moreover, beta-lap markedly suppressed the activation of IkappaB kinase gamma (IKKgamma) and the subsequent phosphorylation of IkappaBalpha, thereby inhibiting NF-kappaB activation. It is concluded that beta-lap suppresses the radiation-induced activation of NF-kappaB by interrupting the involvement of NQO1 in the activation of NF-kappaB, thereby inhibiting the transcription of survival signals. The radiosensitization caused by beta-lap may, in part, be attributed to beta-lap-induced suppression of NF-kappaB activation.
β-拉帕醌（β-lap）的抗癌作用是由于 NAD(P)H：醌氧化还原酶（NQO1）介导的β-拉帕醌氧化还原形式之间的无效循环导致 ROS 的产生和代谢灾难。已经表明，NQO1 对于 TNF 诱导的 NF-κB 激活也是必不可少的，并且β-拉帕醌抑制 TNF 诱导的 NF-κB 激活。我们研究了 NQO1 是否参与以及β-拉帕醌是否通过 A549 人肺癌细胞和 NQO1 敲低 A549 细胞（shNQO1 A549 细胞）抑制辐射诱导的 NF-κB 激活。用 4 Gy 照射 A549 细胞可明显增加 NF-κB 的 DNA 结合活性，但在 shNQO1 A549 细胞中则不然，这表明 NQO1 在辐射诱导的 NF-κB 激活中起关键作用。用 10 µmβ-拉帕醌处理 4 h 几乎完全消除了辐射诱导的 NF-κB 激活增加以及 NF-κB 靶基因如 bcl2、gadd45beta 和 cyclinD1 的转录。此外，β-拉帕醌明显抑制了 IkappaB 激酶γ（IKKγ）的激活以及随后的 IkappaBα磷酸化，从而抑制了 NF-κB 的激活。结论是，β-拉帕醌通过中断 NQO1 在 NF-κB 激活中的参与来抑制 NF-κB 的辐射诱导激活，从而抑制生存信号的转录。β-拉帕醌引起的放射增敏作用可能部分归因于β-拉帕醌诱导的 NF-κB 激活抑制。
