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NF-kappa B inhibition enhances caspase-3 degradation of Akt1 and apoptosis in response to camptothecin

机译：NF-κB抑制增强喜树碱响应的caspase-3降解和细胞凋亡

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DNA damaging agents, such as camptothecin, and ionizing radiation (IR), can induce both NF-kappa B 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-kappa B 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-kappa B inhibitor. In contrast, activation of NF-kappa B but not of caspase-3 by CPT could be found in normal MRC5CV1cells. NF-kappa B inhibition by Pro 1, dominant negative mutant I kappa B alpha (S32/36) or p65 (N250), however, induced the caspase-3 activation in the normal cells, indicating the role of ATM-mediated NF-kappa B 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-kappa B 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-kappa B activation, and that Akt1 degradation be necessarily required for this apoptotic process. (c) 2007 Elsevier Inc. All rights reserved.
机译：DNA破坏剂（例如喜树碱）和电离辐射（IR）既可以诱导NF-κB活化，又可以诱导细胞凋亡，但是，它们之间的调控机制尚不清楚。在本研究中，我们发现当将共济失调毛细血管扩张突变（ATM）缺陷的细胞用于CPT诱导凋亡时，Akt1会被降解。虽然在ATM缺失的AT5BIVA细胞中未检测到CPT诱导的NF-κB活化，但发生了caspase-3活化，并且通过用NF-κB抑制剂蛋白酶体抑制剂1（Pro1）预处理进一步增强了caspase-3活化。相反，在正常的MRC5CV1细胞中可以发现CPT激活NF-κB，而不激活caspase-3。 Pro 1对NF-κB的抑制作用是由显性负突变I kappa B alpha（S32 / 36）或p65（N250）引起的，在正常细胞中诱导了caspase-3的激活，表明ATM介导的NF-κB的作用。 B激活抵抗细胞凋亡。另一方面，有趣的是，CPT显着降低了Akt1的水平，而Pro1预处理可在AT5BIVA细胞中进一步增强Akt1的水平。然而，在MRC5CV1细胞中，只有将CPT和NF-κB抑制剂与细胞共同处理才能降低Akt1的水平，这通过DEVD-cho处理得以逆转，表明caspase-3介导的Akt1降解。此外，尽管与AT5BIVA相比，MRC5CV1细胞对CPT的抵抗力强得多，但渥曼青霉素和LY294002显着提高了MRC5CV1细胞对CPT的化学敏感性。考虑到越来越多的证据表明Akt是一种有前途的抗癌治疗靶标，所有这些结果表明，DNA损伤诱导的细胞凋亡可以由ATM介导的NF-κB激活来调节，并且该凋亡过程必须要求Akt1降解。 （c）2007 Elsevier Inc.保留所有权利。

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