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KMID : 0620920100420050327
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Experimental & Molecular Medicine
2010 Volume.42 No. 5 p.327 ~ p.334
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β-Lapachone suppresses radiation-induced activation of nuclear factor-κB
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Dong Guang-Zhi
Oh Eun-Taex
Lee Hye-Mi
Park Moon-Taek
Song Chang-Won
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Abstract
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Anticancer effects of β-lapachone (β-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 β-lap. It has been shown that NQO1 is also essential for the TNF-induced activation of NF-κB and that β-lap suppresses the TNF-induced NF-κB activation. We investigated whether or not NQO1 is involved and β-lap suppresses the radiation-induced NF-κB 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-κB in A549 cells, but not in the shNQO1 A549 cells, thus demonstrating that NQO1 plays a pivotal role in irradiation-induced NF-κB activation. Treatment with 10 μM β-lap for 4 h almost completely abrogated the radiation-induced increase in NF-κB activation and the transcription of NF-κB target genes such as bcl2, gadd45β and cyclinD1. Moreover, β-lap markedly suppressed the activation of IκB kinase γ (IKKγ) and the subsequent phosphorylation of IκBα, thereby inhibiting NF-κB activation. It is concluded that β-lap suppresses the radiation-induced activation of NF-κB by interrupting the involvement of NQO1 in the activation of NF-κB, thereby inhibiting the transcription of survival signals. The radiosensitization caused by β-lap may, in part, be attributed to β-lap-induced suppression of NF-κB activation.
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KEYWORD
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ionizing radiation, NAD(P)H:quinone oxidoreductase, NF-κB, β-lapachone
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