Park Hyung Sun, Yun Yunha, Kim Cha Soon, Yang Kwang Hee, Jeong Meeseon, Ahn Sung Kwan, Jin Young-Woo, Nam Seon Young
Radiation Health Research Institute, Korea Hydro & Nuclear Power Co. Ltd., Seoul 132-703, Republic of Korea.
Eur J Cell Biol. 2009 Oct;88(10):563-75. doi: 10.1016/j.ejcb.2009.05.004. Epub 2009 Jul 16.
Although AKT activation leads to the activation of various pathways related to cell survival, the roles of AKT in modulating cellular responses induced by ionizing radiation in normal human cells remain unclear. Here we show that low-dose radiation of 0.05Gy did not affect cell death, but high-dose radiation (> 0.2Gy) induced apoptosis through the activation of caspases and acinus cleavage. Ionizing radiation induced acinus phosphorylation via AKT activation. Thus, we examined the effect of AKT activation on radiation-induced cell death using CCD-18Lu cells transduced with a retroviral vector expressing constitutively active AKT (CA-AKT). The overexpression of CA-AKT rendered the cells resistant to ionizing radiation and prevented the proteolytic cleavage of acinus via phosphorylation. In addition, overexpression of CA-AKT resulted in the upregulation of acinus expression by activation of the NF-kappaB pathway. On the other hand, suppression of endogenous AKT expression by siRNA resulted in the reduction of acinus expression and enhanced the radiation-induced apoptosis in both CCD-18Lu and IM-9 cells. Our results suggest that AKT activation inhibits cell death during radiation-induced apoptosis through the regulation of phosphorylation and expression of acinus. The AKT/NF-kappaB/acinus pathway functions as one of the important regulatory mechanisms required for modulating ionizing radiation sensitivity.
尽管AKT激活会导致各种与细胞存活相关的信号通路被激活，但AKT在调节正常人细胞中电离辐射诱导的细胞反应中的作用仍不清楚。在此我们表明，0.05Gy的低剂量辐射不影响细胞死亡，但高剂量辐射（>0.2Gy）通过激活半胱天冬酶和腺泡裂解诱导细胞凋亡。电离辐射通过激活AKT诱导腺泡磷酸化。因此，我们使用表达组成型活性AKT（CA-AKT）的逆转录病毒载体转导的CCD-18Lu细胞，研究了AKT激活对辐射诱导的细胞死亡的影响。CA-AKT的过表达使细胞对电离辐射产生抗性，并通过磷酸化阻止腺泡的蛋白水解裂解。此外，CA-AKT的过表达通过激活NF-κB信号通路导致腺泡表达上调。另一方面，通过siRNA抑制内源性AKT表达导致腺泡表达减少，并增强了CCD-18Lu和IM-9细胞中辐射诱导的细胞凋亡。我们的结果表明，AKT激活通过调节腺泡的磷酸化和表达来抑制辐射诱导的细胞凋亡过程中的细胞死亡。AKT/NF-κB/腺泡信号通路是调节电离辐射敏感性所需的重要调节机制之一。
