A critical role for AKT activation in protecting cells from ionizing radiation-induced apoptosis and the regulation of acinus gene expression.
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.
Park
Hyung Sun
HS
Radiation Health Research Institute, Korea Hydro & Nuclear Power Co. Ltd., Seoul 132-703, Republic of Korea.
Yun
Yunha
Y
Kim
Cha Soon
CS
Yang
Kwang Hee
KH
Jeong
Meeseon
M
Ahn
Sung Kwan
SK
Jin
Young-Woo
YW
Nam
Seon Young
SY
D017209:Apoptosis / Q000528:radiation effects*; D006690:Bisbenzimidazole / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation / Q000528:radiation effects; D005456:Fluorescent Dyes / Q000378:metabolism; D005562:Formazans / Q000378:metabolism; D005786:Gene Expression Regulation / Q000528:radiation effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000378:metabolism
C121310:ACIN1 protein, human; D005456:Fluorescent Dyes; D005562:Formazans; D009687:Nuclear Proteins; D011837:Radiation-Protective Agents; D013778:Tetrazolium Salts; C079782:MTT formazan; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053181:Caspase 8; D006690:Bisbenzimidazole