Inhibition of SOD1 expression by mitomycin C is a non-specific consequence of cellular toxicity.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition that results in the death of the large motor neurons of the brain and spinal cord. Familial ALS accounts for 10% of all ALS cases. Approximately 25% of these cases are due to mutations in the SOD1 gene. Several lines of evidence argue that mutant SOD1 causes ALS by a toxic gain of function. We therefore anticipate that measures that reduce the levels of mutant SOD1 expression should be beneficial in mutant SOD1-associated ALS patients. Mitomycin C (MC) is an antitumor antibiotic previously demonstrated to reduce SOD1 expression in a reporter gene system. We investigated whether MC reduces endogenous SOD1 expression levels both in vitro and in vivo. MC reduced human and rat SOD1 protein levels in vitro, with a concomitant decrease in actin and increase in p53 protein levels, as detected by Western blotting. However, this decrease in SOD1 protein levels was paralleled by a similar decrease in cell viability. In contrast, intracerebroventricular administration of MC to rats and mice failed to produce any effect on brain or spinal cord SOD1 protein levels. Our data indicate the apparent inhibition of SOD1 expression by MC is a non-specific consequence of MC-induced cellular toxicity.
Broom
Wendy J
WJ
Day Neuromuscular Research Laboratory, Massachusetts General Hospital, MGH-East, 114 16th Street, Navy Yard, Charlestown, MA 02129, USA. wbroom@partners.org
Ay
Ilknur
I
Pasinelli
Piera
P
Brown
Robert H
RH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016685:Mitomycin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D000903:Antibiotics, Antineoplastic; C000606290:SOD1 protein, human; D016685:Mitomycin; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020169:Caspases