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Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis
- Source :
- Journal of Cell Science. 116:4409-4417
- Publication Year :
- 2003
- Publisher :
- The Company of Biologists, 2003.
-
Abstract
- Glioma cells that migrate out of the main tumor mass into normal brain tissue contribute to the failure of most gliomas to respond to treatment. Treatments that target migratory glioma cells may enhance the therapeutic response. Multiple lines of evidence suggest that suppression of apoptosis accompanies activation of the migratory phenotype. Here, we determine whether migration and apoptosis are consistently linked in glioma cells and whether manipulation of migration influences cytotoxic therapy-induced apoptosis. Camptothecin and Trail-induced apoptosis were decreased 2-5-fold in actively migrating glioma cells relative to migration-restricted cells. Consistent with a mechanistic link between migration and apoptosis, the dose-response for stimulation of migration on laminin was inversely proportional to apoptosis induction. Treatment of glioma cells with migration inhibitors alone had little effect on basal rates of apoptosis and had little effect on Trail-induced or camptothecin-induced apoptosis in migration-restricted cells. By contrast, migration inhibitors increased camptothecin and Trail-induced apoptosis in actively migrating glioma cells. Migrating glioma cells have increased amounts of phosphorylated Akt and its downstream substrate glycogen synthase kinase-3 relative to migration restricted cells. Treatment of migrating cells with a specific inhibitor of phosphoinositide 3-kinase (PI3-K), LY294002, blocked the phosphorylation of Akt and increased the sensitivity to apoptosis. LY294002 had no effect on the migration of restricted cells. This suggests that migrating glioma cells activate the PI3-K survival pathway, protecting migrating cells from apoptosis. Taken together, these data provide support for a link between migration and apoptosis in glioma cells. In addition, evidence indicates that treatment with migration inhibitors, while not affecting apoptosis-induction in migration-restricted cells, can sensitize migrating glioma cells to cytotoxic agents.
- Subjects :
- Morpholines
Apoptosis
Protein Serine-Threonine Kinases
Biology
TNF-Related Apoptosis-Inducing Ligand
Glycogen Synthase Kinase 3
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Cell Movement
GSK-3
Proto-Oncogene Proteins
Glioma
Tumor Cells, Cultured
medicine
Animals
Humans
Cytotoxic T cell
LY294002
Enzyme Inhibitors
Phosphorylation
neoplasms
Protein kinase B
Phosphoinositide-3 Kinase Inhibitors
Membrane Glycoproteins
Tumor Necrosis Factor-alpha
Integrin beta1
Imidazoles
Cell Biology
medicine.disease
Immunohistochemistry
Cell biology
Enzyme Activation
chemistry
Chromones
Cancer research
Camptothecin
Tumor necrosis factor alpha
Laminin
Signal transduction
Apoptosis Regulatory Proteins
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 14779137 and 00219533
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Science
- Accession number :
- edsair.doi.dedup.....bdccbb6ddcc8ba39b61c4ed54184582f
- Full Text :
- https://doi.org/10.1242/jcs.00712