Manganese superoxide dismutase (SOD2) inhibits radiation-induced apoptosis by stabilization of the mitochondrial membrane.
To define the molecular pathways involved in radiation-induced apoptosis and the role of the mitochondria, 32D cl 3 hematopoietic cells and subclones overexpressing either the human manganese superoxide dismutase (SOD2) transgene (1F2 and 2C6) or BCL2L1 (also known as Bcl-xl) transgene (32D-Bcl-xl) were compared for their response to radiation at the subcellular level, comparing nuclear to mitochondrial localized pathways. All cell lines showed complete detectable DNA repair by 30 min after irradiation, and clearly delayed migration of BAX and active stress-activated protein (SAP) kinases MAPK1 (also known as p38) and MAPK8 (also known as JNK1) to the mitochondria at 3 h. Radioresistant clonal lines 1F2, 2C6 and 32D-Bcl-xl showed significant decreases in mitochondrial membrane permeability, cytochrome C release, caspase 3 and poly(adenosine diphosphate-ribose) polymerase (PARP) activation at 6-12 h, and in apoptosis at 24 h. Since the nuclear-to-cytoplasm events preceding the release of cytochrome C were similar in all cell lines, and increased expression of either the SOD2 or the BCL2L1 transgene provided radiation protection, we conclude that events at the level of the mitochondria are critically involved in radiation-induced apoptosis.
Epperly
Michael W
MW
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA. Epperly+@pitt.edu
Sikora
Christine A
CA
DeFilippi
Stacy J
SJ
Gretton
Joan A
JA
Zhan
Qimin
Q
Kufe
Donald W
DW
Greenberger
Joel S
JS
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D002460:Cell Line; D002999:Clone Cells; D020552:Comet Assay; D003574:Cytochrome c Group / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D007425:Intracellular Membranes / Q000528:radiation effects; D007700:Kinetics; D051379:Mice; D008928:Mitochondria / Q000528:radiation effects*; D010539:Permeability; D011494:Protein Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D011836:Radiation Tolerance; D011994:Recombinant Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D014162:Transfection; D051028:bcl-2-Associated X Protein; D000099156:Superoxide Dismutase 2
D003574:Cytochrome c Group; D011494:Protein Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D013482:Superoxide Dismutase; D051028:bcl-2-Associated X Protein; D000099156:Superoxide Dismutase 2; C494826:BAX protein, human; C494827:Bax protein, mouse