Journal
CELL DEATH AND DIFFERENTIATION
Volume 12, Issue 8, Pages 1066-1077Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4401650
Keywords
PC12 cell apoptosis; differentiation; nerve growth factor; GSH redox imbalance; mitochondrial apoptosis signaling; apoptosis protease activator factor-1
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Funding
- NIDDK NIH HHS [R01 DK044510, R01 DK044510-12, DK 44510] Funding Source: Medline
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We previously showed that tert-butyl hydroperoxide (TBH) induced apoptosis in naive rat pheochromocytoma (nPC12) cells that correlated with cellular redox imbalance and mitochondrial apoptotic signaling. In this study, we tested the hypothesis that differentiation of nPC12 cells results in altered susceptibility to TBH utilizing a model of differentiated PC12 (dPC12) cells induced by nerve growth factor. TBH (100 mu M) induced dPC12 apoptosis (12% at 24 h) at levels lower than naive cells (35%). This resistance was associated with elevated GSH, NADPH (reduced nicotinamide adenine dinucleotide phosphate), TBH metabolism, redox enzyme activities, reduced cellular GSH/GSSG (glutathione disulfide) status and preservation of mitochondrial membrane potential. Altering cellular GSH with ethacrynic acid or N-acetylcysteine, respectively, exacerbated or protected against dPC12 apoptosis. dPC12 apoptosis was mediated by caspase-9 and -3 activation and apoptosis protease activator protein-1 (Apaf-1) expression. These results show that nPC12 transition to dPC12 cells afforded protection against oxidative challenge due to maintenance of reduced GSH/GSSG and decreased Apaf-1 expression.
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