Antizyme suppression leads to an increment of the cellular redox potential and an induction of HIF-1alpha: its involvement in resistance to gamma-radiation.
The mammalian antizyme (AZ) promotes ubiqutin-independent degradation of ornithine decarboxylase, a key enzyme in polyamine biosynthesis. This study shows that AZ suppression in human lung carcinoma A549 cells caused growth defects and death, but made the cells resistant to DNA damaging agents such as gamma-radiation and cisplatin. In these cells, the cellular redox potential (glutathione/glutathione disulfide [GSH/GSSG] ratio) was increased and thus intracellular reactive oxygen species were severely diminished, which might cause growth defects and cell death. The increase of cellular redox potential was mainly caused by dramatic increase of the cytoplasmic nicotinamide adenine dinucleotide phosphate (NADP)(+)-dependent isocitrate dehydrogenase, which generates the reducing equivalents NADPH. In the AZ-suppressed cells, the hypoxia inducible factor 1alpha (HIF-1alpha) was also increased. As in other cases which showed an increment of HIF-1alpha and the cellular redox potential, the AZ-suppressed cells showed resistance to gamma-radiation and anticancer drugs. Therefore, these facts might be considered as important for the use of radio- and chemotherapy on tumor cells which show an unbalance in their polyamine levels.
Kim
Jin Sik
JS
Department of Radiation Biology, Environment Radiation Research Group, Korea Atomic Energy Research Institute, Yusong, Daejeon, Korea.
Kim
Tae Lim
TL
Cho
Eun Wie
EW
Paik
Sang Gi
SG
Chung
Hai Won
HW
Kim
In Gyu
IG
D045744:Cell Line, Tumor; D002470:Cell Survival; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D005434:Flow Cytometry; D005720:Gamma Rays; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000378:metabolism*; D008954:Models, Biological; D009249:NADP / Q000737:chemistry; D010084:Oxidation-Reduction; D011073:Polyamines / Q000737:chemistry; D034622:RNA Interference; D017382:Reactive Oxygen Species
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011073:Polyamines; D017382:Reactive Oxygen Species; D009249:NADP; D007521:Isocitrate Dehydrogenase; C039355:isocitrate dehydrogenase (NADP+)