beta-Lapachone suppresses radiation-induced activation of nuclear factor-kappaB.
10.3858/emm.2010.42.5.034
- Author:
Guang Zhi DONG
1
;
Eun Taex OH
;
Hyemi LEE
;
Moon Taek PARK
;
Chang Won SONG
;
Heon Joo PARK
Author Information
1. Department of Microbiology, and Center for Advanced Medical Education by BK21 Project, College of Medicine, Inha University, Incheon 400-712, Korea. park001@inha.ac.kr
- Publication Type:Original Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
- Keywords:
ionizing radiation;
NAD(P)H:quinone oxidoreductase;
NF-kappaB;
beta-lapachone
- From:Experimental & Molecular Medicine
2010;42(5):327-334
- CountryRepublic of Korea
- Language:English
-
Abstract:
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 micrometer 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.
