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  • Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor.

Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor.

Molecular cancer therapeutics (2009-05-07)
Thamara J Abouantoun, Tobey J MacDonald
ABSTRACT

Platelet-derived growth factor (PDGF) receptor (PDGFR) expression correlates with metastatic medulloblastoma. PDGF stimulation of medulloblastoma cells phosphorylates extracellular signal-regulated kinase (ERK) and promotes migration. We sought to determine whether blocking PDGFR activity effectively inhibits signaling required for medulloblastoma cell migration and invasion. DAOY and D556 human medulloblastoma cells were treated with imatinib mesylate (Gleevec), a PDGFR tyrosine kinase inhibitor, or transfected with small interfering RNA (siRNA) to PDGFRB to test the effects of blocking PDGFR phosphorylation and expression, respectively. PDGFR cell signaling, migration, invasion, survival, and proliferation following PDGF-BB stimulation, with and without PDGFR inhibition, were measured. PDGF-BB treatment of cells increased PDGFRB, Akt and ERK phosphorylation, and transactivated epidermal growth factor receptor (EGFR), which correlated with enhanced migration, survival, and proliferation. Imatinib (1 μmol/L) treatment of DAOY and D556 cells inhibited PDGF-BB- and serum-mediated migration and invasion at 24 and 48 h, respectively, and concomitantly inhibited PDGF-BB activation of PDGFRB, Akt, and ERK but increased PTEN expression and activity. Imatinib treatment also induced DAOY cell apoptosis at 72 h and inhibited DAOY and D556 cell proliferation at 48 h. siRNA silencing of PDGFRB similarly inhibited signaling, migration, and survival and both siRNA and imatinib treatment inhibited PDGF-BB-mediated EGFR transactivation, indicating that the effects of imatinib treatment are specific to PDGFRB target inhibition. These results indicate that PDGFRB tyrosine kinase activity is critical for migration and invasion of medulloblastoma cells possibly by transactivating EGFR; thus, imatinib may represent an important novel therapeutic agent for the treatment of medulloblastoma.

MATERIALS
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Product Description

Sigma-Aldrich
QCM ECMatrix Cell Invasion Assay, 24-well (8 µm), colorimetric, The CHEMICON Cell Invasion Assay Kit uses a 24-well plate, with 8 um pores, which provides an efficient system for evaluating the invasion of tumor cells through a basement membrane model.
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CaspaTag Caspase 8 In Situ Assay Kit 25, Fluorescein, The CaspaTag Caspase-8 In Situ Assay Kit, Fluorescein for flow cytometry is a fluorescent-based assay for detection of active caspase-8 in cells undergoing apoptosis.
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QCM Haptotaxis Cell Migration Assay -Fibronectin, 24-well, colorimetric, The QCM Haptotaxis Cell Migration Assay, 24-well plate -Fibronectin, Colorimetric is ideal for the study of epithelial & fibroblast cell haptotaxis.