Beta-lapachone suppresses radiation-induced activation of nuclear factor-kappaB.
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.
Dong
Guang Zhi
GZ
Department of Microbiology, and Center for Advanced Medical Education by BK21 Project, College of Medicine, Inha University, Incheon 400-712, Korea.
Oh
Eun Taex
ET
Lee
Hyemi
H
Park
Moon Taek
MT
Song
Chang Won
CW
Park
Heon Joo
HJ
D000943:Antigens, Differentiation / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D019938:Cyclin D1 / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects* / Q000378:metabolism* / Q000528:radiation effects; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D009285:Naphthoquinones / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D019938:Cyclin D1; D051550:I-kappa B Kinase; D016660:NAD(P)H Dehydrogenase (Quinone); D016328:NF-kappa B; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D011838:Radiation-Sensitizing Agents; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C014638:beta-lapachone; C447479:NQO1 protein, human