TNF-α Induces Apoptosis Through JNK/Bax-Dependent Pathway in Differentiated, but not Naïve PC12 Cells

Abstract

Differentiated PC12 cells have been used widely as a model for the analysis of neuronal degeneration. Some evidences showed that differentiated PC12 cells were more sensitive than naïve PC12 against apoptosis stimuli. However, the apoptosis mechanism of both types of PC12 cells was not fully known. In this study, the signaling pathways involved in tumor necrosis factor-a (TNFa)-induced apoptosis in living differentiated and naïve PC12 cells were investigated using confocal microscope for the first time. Our results showed that during TNFa-induced apoptosis, Bax translocation to mitochondria and cytochrome C (Cyt c) release from mitochondria were observed in differentiated PC12 cells, but not in naïve PC12 cells. Furthermore, the mRNA levels of bim, c-Jun N-terminal protein kinase 1 and 2 (JNK1 and JNK2) increased noticeably in differentiated PC12 cells. The apoptosis induced by TNFa was inhibited by Z-IETD-fmk (specific inhibitor of caspase-8) but not SP600125 (specific inhibitor of JNK) in naïve PC12 cells. While in differentiated PC12 cells, the process of apoptosis could only be inhibited effectively by Z-IETD-fmk and SP600125 cotreatment, and SP600125 inhibited the Bax translocation to mitochondria implying that JNK mediated activation of Bax. The experimental data strongly demonstrated that TNFa induced apoptosis through JNK/ Bax-dependent pathway in differentiated, but not naïve PC12 cells.

Calcium overload is essential for the acceleration of staurosporine-induced cell death following neuronal differentiation in PC12 cells

“…The cell death provoked by 0.2 μM staurosporine progressed more rapidly over time in differentiated PC12 cells than in undifferentiated cells ( Figure 1B). Therefore, our findings are in agreement with those recently reported by Zhang and colleagues (Oberdoerster and Rabin, 1999;Zhang et al, 2007), but not with those reported by Ekshyyan and Aw (Ekshyyan et al, 2005). Ekshyyan and Aw demonstrated that the transition of undifferentiated PC12 cells into differentiated cells affords protection against oxidative stress.…”

“…Several controversial reports show that neurotoxic effect was different between undifferentiated and differentiated phenotypes of PC12 cells (Oberdoerster and Rabin, 1999;Okouchi et al, 2005;Zhang et al, 2007).…”

“…Previously, neuronally differentiated PC12 cells appeared to be more sensitive to apoptotic stimuli, such as TNFα and ethanol, than undifferentiated cells (Oberdoerster and Rabin, 1999;Zhang et al, 2007). In the present study, 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.…”

“…Previously, 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). On the other hand, however, a carbonyl stressor (methylglyoxal) was shown to induce apoptosis more robustly in undifferentiated PC12 cells (Okouchi et al, 2005).…”

JNK implication in adipocyte-like cell death induced by chemotherapeutic drug cisplatin

“…In this study, the pretreatment of cells with JNK inhibitor SP600125 decreased cisplatin induced activation of c-Jun phosphorylation but increased Bax expression and subsequent apoptotic cell death. It is known that participation of Bax in apoptosis occurs via protein expression level and conformational changes, cleavage and translocation to mitochondria (Okuno et al, 2004;Zhang et al, 2007). The results obtained by us prove that cisplatin-induced JNK signaling in adipocytes may influence Bax expression regulation and that JNK is an upstream Bax regulator.…”