NF-κB inhibition enhances caspase-3 degradation of Akt1 and apoptosis in response to camptothecin = Camptothecin 유도 NF-kB 저해에 의한 caspase-3 매개 Akt1 분해와 세포사멸 증진

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Title
NF-κB inhibition enhances caspase-3 degradation of Akt1 and apoptosis in response to camptothecin = Camptothecin 유도 NF-kB 저해에 의한 caspase-3 매개 Akt1 분해와 세포사멸 증진
Author(s)
Long He; Bo Yeon Kim; K A Kim; Osong Kwon; Sun Ok Kim; Eun Young Bae; Myung Sun Lee; Min-Soo Kim; M Jung; A Moon; K Bae; Jong Seog Ahn
Bibliographic Citation
Cellular Signalling, vol. 19, no. 8, pp. 1713-1721
Publication Year
2007
Abstract
DNA damaging agents, such as camptothecin, and ionizing radiation (IR), can induce both NF-κB activation and apoptosis, however, the mechanism of their inter-regulation is not yet clear. In the present study, we discovered that Akt1 is degraded when cells deficient in Ataxia Telangiectasia mutated (ATM) were treated to CPT for apoptosis induction. While CPT-induced NF-κB activation could not be detected in ATM-deficient AT5BIVA cells, caspase-3 activation occurred and was even further enhanced by pretreatment with proteasome inhibitor-1 (Pro1), a NF-κB inhibitor. In contrast, activation of NF-κB but not of caspase-3 by CPT could be found in normal MRC5CV1 cells. NF-κB inhibition by Pro1, dominant negative mutant IκBα (S32/36) or p65 (N250), however, induced the caspase-3 activation in the normal cells, indicating the role of ATM-mediated NF-κB activation against cell apoptosis. On the other hand, interestingly, CPT significantly reduced the level of Akt1, this effect further enhanced by Pro1 pretreatment in AT5BIVA cells. In MRC5CV1 cells, however, Akt1 level could be reduced only when CPT and NF-κB inhibitors were co-treated to the cells, and this reversed by DEVD-cho treatment, demonstrating the caspase-3-mediated Akt1 degradation. Moreover, although MRC5CV1 cells were much more resistant to CPT compared with AT5BIVA, wortmannin and LY294002 significantly increased the chemosensitivity of MRC5CV1 cells to CPT. Given the accumulating evidences demonstrating Akt as a promising anticancer therapeutic target, all these results suggest that DNA damage induced apoptosis could be regulated by ATM-mediated NF-κB activation, and that Akt1 degradation be necessarily required for this apoptotic process.
Keyword
AktApoptosisATMCamptothecinNF-κBProteasome
ISSN
0898-6568
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.cellsig.2007.03.006
Type
Article
Appears in Collections:
Ochang Branch Institute > Anticancer Agent Research Center > 1. Journal Articles
Jeonbuk Branch Institute > Microbial Biotechnology Research Center > 1. Journal Articles
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