Abstract
Differentiation of neuronal cells has been shown to accelerate stress-induced cell death, but the underlying mechanisms are not completely understood. Here, we find that early and sustained increase in cytosolic ([Ca2(+)]c) and mitochondrial Ca2(+) levels ([Ca2(+)]m) is essential for the increased sensitivity to staurosporine- induced cell death following neuronal differentiation in PC12 cells. Consistently, pretreatment of differentiated PC12 cells with the intracellular Ca2(+)-chelator EGTA-AM diminished staurosporine-induced PARP cleavage and cell death. Furthermore, Ca2(+) overload and enhanced vulnerability to staurosporine in differentiated cells were prevented by Bcl-XL overexpression. Our data reveal a new regulatory role for differentiation-dependent alteration of Ca2(+) signaling in cell death in response to staurosporine.
Highlights
It has been reported that PC12 cells differentiated into sympathetic neurons in response to nerve growth factor (NGF) are more sensitive to apoptotic stimuli, such as TNF-α and ethanol, than undifferentiated PC12 cells (Oberdoerster et al, 1999; Zhang et al, 2007)
We tested if NGFinduced neuronal differentiation in PC12 cells accelerates cell death in response to staurosporine, which has been used as a common inducer of cell death in almost all cell types
Since the mitochondrial cytochrome c released into the cytosol has been identified as an apoptosis initiation molecule (Desagher et al, 2000), we examined whether staurosporine accelerated the release of mitochondrial cytochrome c into the cytosol in neuronally differentiated PC12 cells
Summary
It has been reported that PC12 cells differentiated into sympathetic neurons in response to nerve growth factor (NGF) are more sensitive to apoptotic stimuli, such as TNF-α and ethanol, than undifferentiated PC12 cells (Oberdoerster et al, 1999; Zhang et al, 2007). A carbonyl stressor (methylglyoxal) was shown to induce apoptosis more robustly in undifferentiated PC12 cells (Okouchi et al, 2005). These different reports suggest that mechanisms involved in death pathways are divided between neurotoxic factors and may be significantly influenced by cellular phenotypes. Numerous findings have suggested that perturbation of Ca2+ signaling contributes to many agerelated neurodegenerative disorders, including: Parkinson's Disease (PD), Huntington’s Disease (HD), ischemic stroke, and amyotrophic lateral sclerosis (Beal, 1998; Rodnitzky, 1999; Simpson, et al, 2002)
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