Tau protein is involved in the apoptotic process induced by anti-microtubule agents on neuroblastoma cells
S Guise1, D Braguer, M Remacle-Bonnet
1UPRES-A CNRS 6032, Université de la Méditerranée, Marseille, France.
Abstract:
Paclitaxel and docetaxel are potent anti-microtubule and antimitotic agents that induce apoptosis in bone marrow-derived cells and epithelial cells. This study examined apoptosis induced by anti-microtubule agents in the neuroblastoma SK-N-SH cell line with a special focus on tau protein which is one of the main Microtubule-Associated- Proteins (MAPs) in neuronal cells. In time, treatment with 1 microM paclitaxel successively induced formation of bundles, then pseudo-asters concomitantly with mitotic block and phosphorylation of bcl-2 (48 h), then phosphorylation of tau and externalization of phosphatidylserine at the early phase of apoptosis (72 h) and finally DNA fragmentation (96 h). Similar results were obtained with 0.5 microM vinorelbine. Paclitaxel induced a lower increase in tau phosphorylation in differentiated SK-N-SH/RA+ cells which are less sensitive to apoptosis. Moreover, doxorubicin whose mechanism of action is independent of microtubules also induced immunostaining of tau at 72 h treatment. In conclusion, our results on neuroblastoma cells show that overexpression of hyperphosphorylated tau is involved in the apoptotic process induced by anti-microtubule agents and may be extended to others cytostatic drugs. Thus, tau protein may play a role in the cellular events observed in neuroblastoma cells undergoing apoptosis.
Insights
Anti-microtubule chemotherapy agents induce apoptosis in neuroblastoma cells by promoting tau protein hyperphosphorylation. This tau modification is linked to cell death, suggesting a role in drug-induced apoptosis.
Area of Science:
- Cell Biology
- Neuroscience
- Pharmacology
Background:
- Paclitaxel and docetaxel are established anti-microtubule and antimitotic drugs.
- These agents induce apoptosis in various cell types, including bone marrow and epithelial cells.
- Neuroblastoma is a pediatric cancer with significant unmet therapeutic needs.
Purpose of the Study:
- To investigate apoptosis induced by anti-microtubule agents in the neuroblastoma SK-N-SH cell line.
- To specifically examine the role of tau protein, a key Microtubule-Associated Protein (MAP), in this process.
- To understand the temporal sequence of events leading to apoptosis.
Main Methods:
- Treatment of SK-N-SH cells with paclitaxel (1 microM) or vinorelbine (0.5 microM).
- Assessment of cellular events including microtubule bundling, pseudo-aster formation, mitotic block, bcl-2 phosphorylation, tau phosphorylation, phosphatidylserine externalization, and DNA fragmentation.
- Comparison of drug effects on differentiated, less sensitive SK-N-SH/RA+ cells.
- Investigation of doxorubicin's effect on tau immunostaining.
Main Results:
- Paclitaxel treatment induced a cascade of events: microtubule bundling, pseudo-asters, mitotic block, bcl-2 phosphorylation (48h), tau phosphorylation and phosphatidylserine externalization (72h), and DNA fragmentation (96h).
- Similar results were observed with vinorelbine.
- Differentiated SK-N-SH/RA+ cells showed reduced tau phosphorylation in response to paclitaxel.
- Doxorubicin, a non-microtubule targeting agent, also induced tau immunostaining.
Conclusions:
- Hyperphosphorylated tau is implicated in the apoptotic process of neuroblastoma cells treated with anti-microtubule agents.
- The findings suggest that tau protein plays a significant role in the cellular events of apoptosis in neuroblastoma.
- The observed tau hyperphosphorylation may extend to other cytostatic drug treatments.
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