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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

Authors 

Long HeBo Yeon KimK A KimOsong KwonSun Ok KimEun Young BaeMyung Sun LeeMin-Soo KimM JungA MoonK BaeJong Seog Ahn

Publisher 

Elsevier

Issue Date 

2007

Citation 

Cellular Signalling, vol. 19, no. 8, pp. 1713-1721

Keywords 

AktapoptosisATMcamptothecinNF-κBproteasomecaspase 3I kappa B betaimmunoglobulin enhancer binding protein

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.

ISSN 

0898-6568

Link 

http://dx.doi.org/10.1016/j.cellsig.2007.03.006

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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