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Cross-talk in nucleotide signaling in glioma C6 cells
Dorota Wypych1, Jolanta Barańska
1Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St, PL 02-093, Warsaw, Poland. d.wypych@nencki.gov.pl
Abstract:
The chapter is focused on the mechanism of action of metabotropic P2Y nucleotide receptors: P2Y(1), P2Y(2), P2Y(12), P2Y(14) and the ionotropic P2X(7) receptor in glioma C6 cells. P2Y(1) and P2Y(12) both respond to ADP, but while P2Y(1) links to PLC and elevates cytosolic Ca(2+) concentration, P2Y(12) negatively couples to adenylate cyclase, maintaining cAMP at low level. In glioma C6, these two P2Y receptors modulate activities of ERK1/2 and PI3K/Akt signaling and the effects depend on physiological conditions of the cells. During prolonged serum deprivation, cell growth is arrested, the expression of the P2Y(1) receptor strongly decreases and P2Y(12) becomes a major player responsible for ADP-evoked signal transduction. The P2Y(12) receptor activates ERK1/2 kinase phosphorylation (a known cell proliferation regulator) and stimulates Akt activity, contributing to glioma invasiveness. In contrast, P2Y(1) has an inhibitory effect on Akt pathway signaling. Furthermore, the P2X(7) receptor, often responsible for apoptotic fate, is not involved in Ca(2+)elevation in C6 cells. The shift in nucleotide receptor expression from P2Y(1) to P2Y(12) during serum withdrawal, the cross talk between both receptors and the lack of P2X(7) activity shows the precise self-regulating mechanism, enhancing survival and preserving the neoplastic features of C6 cells.
Insights
In glioma cells, P2Y12 receptors promote invasiveness by activating ERK1/2 and Akt signaling, especially during serum deprivation when P2Y1 receptors decrease. This highlights a survival mechanism in C6 glioma cells.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Glioma cells exhibit complex signaling pathways influencing their growth and invasiveness.
- Nucleotide receptors, including P2Y and P2X families, play crucial roles in cellular communication and function.
- Understanding specific receptor mechanisms in glioma is vital for developing targeted therapies.
Purpose of the Study:
- To elucidate the mechanism of action of specific P2Y (P2Y1, P2Y2, P2Y12, P2Y14) and P2X (P2X7) receptors in C6 glioma cells.
- To investigate how these receptors modulate intracellular signaling pathways like ERK1/2 and PI3K/Akt under varying cellular conditions.
- To determine the role of nucleotide receptors in glioma cell survival and neoplastic feature preservation.
Main Methods:
- Focus on the functional characterization of P2Y1, P2Y12, and P2X7 receptors in C6 glioma cells.
- Analysis of ADP-evoked signaling cascades, including Ca(2+) elevation, PLC, adenylate cyclase, cAMP levels, ERK1/2 phosphorylation, and Akt activity.
- Examination of receptor expression and signaling modulation during prolonged serum deprivation.
Main Results:
- P2Y1 and P2Y12 receptors differentially regulate ERK1/2 and PI3K/Akt signaling pathways in C6 glioma cells.
- During serum deprivation, P2Y1 expression decreases, while P2Y12 becomes dominant, activating ERK1/2 and Akt, thus promoting invasiveness.
- The P2X7 receptor in C6 cells does not contribute to Ca(2+) elevation, and its role in apoptosis appears distinct from its typical function.
- A shift in nucleotide receptor expression (P2Y1 to P2Y12) during serum withdrawal suggests a self-regulating survival mechanism.
Conclusions:
- The interplay between P2Y1 and P2Y12 receptors, particularly the upregulation of P2Y12 under stress, enhances C6 glioma cell survival and maintains neoplastic characteristics.
- These findings reveal a sophisticated self-regulation mechanism in glioma cells mediated by nucleotide receptors.
- Targeting these specific nucleotide receptor pathways could offer novel therapeutic strategies for glioma treatment.
