Overexpression of MnSOD protects murine fibrosarcoma cells (FSa-II) from apoptosis and promotes a differentiation program upon treatment with 5-azacytidine: involvement of MAPK and NFkappaB pathways.
Stable transfection of neomycin and human manganese superoxide dismutase (MnSOD2) expression plasmids into a murine fibrosarcoma cell line (FSa-II) was previously done in our laboratory. Treatment with 10 microM 5-azacytidine induced apoptosis in the control cell line (NEO), whereas the MnSOD-overexpressing cell line (SOD-H) demonstrated differentiated-appearing morphology. The levels of the myogenic transcription factor, MyoD, and the muscle-specific marker, alpha-actin, were increased over time with 5-azacytidine treatment in the SOD-H cell line. Nuclear transcription factor NFkappaB was activated in the SOD-H cell line, whereas inhibition of NFkappaB activation reduced the levels of MyoD and alpha-actin. Members of mitogen-activated protein kinase pathway and the Raf1/MEK/ERK cascade were shown to play a positive role in this event. Overexpression of MnSOD not only can protect cells from the toxic effects of 5-azacytidine, but can also promote the fibrosarcoma cells to enter a differentiation program.
Zhao
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Y
Graduate Center for Toxicology, University of Kentucky, Lexington 40536, USA.
Kiningham
K K
KK
Lin
S M
SM
St Clair
D K
DK
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001374:Azacitidine / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D007700:Kinetics; D020935:MAP Kinase Signaling System; D051379:Mice; D008809:Mice, Inbred C3H; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017570:MyoD Protein / Q000096:biosynthesis; D016328:NF-kappa B / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000199:Actins; D000964:Antimetabolites, Antineoplastic; D017570:MyoD Protein; D016328:NF-kappa B; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D001374:Azacitidine