Open Accessβ-Lapachone suppresses radiation-induced activation of nuclear factor-κB
Author(s) -
Guang Zhi Dong,
Eun Taex Oh,
Hyemi Lee,
Moon Taek Park,
Chang W. Song,
Heon Joo Park
Publication year - 2010
Publication title -
experimental and molecular medicine/experimental and molecular medicine
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 2.703
H-Index - 82
eISSN - 2092-6413
pISSN - 1226-3613
DOI - 10.3858/emm.2010.42.5.034
Subject(s) - a549 cell , transcription factor , chemistry , nfkb1 , nf κb , phosphorylation , beta (programming language) , kinase , microbiology and biotechnology , tumor necrosis factor alpha , transcription (linguistics) , apoptosis , cancer research , biology , endocrinology , biochemistry , gene , computer science , programming language , linguistics , philosophy
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.