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Characterization of ATP-induced cell death in the GL261 mouse glioma
Alessandra S K Tamajusuku1, Emilly S Villodre, Romela Paulus
1Departamento de Biofísica, Porto Alegre, RS, Brazil.
Abstract:
Gliomas have one of the worst prognosis among cancers. Their resistance to cell death induced by endogenous neurotoxic agents, such as extracellular ATP, seems to play an important role in their pathobiology since alterations in the degradation rate of extracellular ATP drastically affects glioma growth in rats. In the present work we characterized the mechanisms of cell death induced by extracellular ATP in a murine glioma cell line, GL261. ATP and BzATP, a P2X7 agonist, induced cell death at concentrations that are described to activate the P2X7 receptor in mouse. oATP, an antagonist of P2X7, blocked the ATP-induced cell death. Agonists of purinergic receptors expressed in GL261 such as adenosine, ADP, UTP did not cause any cell death, even at mM concentrations. A sub-population of cells more sensitive to ATP expressed more P2X7 when compared to a less sensitive subpopulation. Accordingly, RNA interference of the P2X7 receptor drastically reduced ATP-induced cell death, suggesting that this receptor is necessary for this effect. The mechanism of ATP-induced cell death is predominantly necrotic, since cells presented shrinkage accompanied by membrane permeabilization, but not apoptotic, since no phosphatidylserine externalization or caspase activity was observed. These data show the importance of P2X7 in ATP-induced cell death and shed light on the importance of ATP-induced cell death in glioma development.
Insights
Extracellular ATP induces glioma cell death primarily through necrosis, mediated by the P2X7 receptor. This finding highlights a potential therapeutic target for aggressive brain tumors.
Area of Science:
- Neuro-oncology
- Cellular Biology
- Biochemistry
Background:
- Gliomas are aggressive brain tumors with poor prognoses.
- Resistance to cell death pathways contributes to glioma progression.
- Extracellular ATP (adenosine triphosphate) has been implicated in glioma pathobiology.
Purpose of the Study:
- To investigate the mechanisms of cell death induced by extracellular ATP in a murine glioma cell line (GL261).
- To determine the role of the P2X7 receptor in ATP-mediated glioma cell death.
- To elucidate the type of cell death (apoptotic vs. necrotic) induced by extracellular ATP.
Main Methods:
- Utilized GL261 murine glioma cells.
- Administered ATP and BzATP (P2X7 agonist) to induce cell death.
- Employed oATP (P2X7 antagonist) to block ATP-induced cell death.
- Used RNA interference to reduce P2X7 receptor expression.
- Assessed cell death markers, including phosphatidylserine externalization and caspase activity.
Main Results:
- ATP and BzATP induced cell death in GL261 cells.
- P2X7 receptor activation was necessary for ATP-induced cell death, as shown by antagonist and RNA interference studies.
- A subpopulation of cells with higher P2X7 expression was more sensitive to ATP.
- ATP-induced cell death was predominantly necrotic, characterized by cell shrinkage and membrane permeabilization, not apoptosis.
Conclusions:
- The P2X7 receptor is crucial for mediating extracellular ATP-induced cell death in glioma cells.
- The findings suggest that necrosis, rather than apoptosis, is the primary mechanism of cell death.
- Targeting P2X7-mediated cell death could offer a novel therapeutic strategy for gliomas.
