Investigating the mechanism by which the platelet-derived growth factor receptor promotes metastasis in medulloblastoma

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dc.contributor.author AbouAntoun, Thamara Jihad
dc.date.accessioned 2017-12-18T10:23:04Z
dc.date.available 2017-12-18T10:23:04Z
dc.date.copyright 2008 en_US
dc.date.issued 2017-12-18
dc.identifier.uri http://hdl.handle.net/10725/6823
dc.description.abstract Expression of the platelet-derived growth factor receptor (PDGFR) correlates with metastatic medulloblastoma and PDGF treatment of medulloblastoma cells activates the pro-survival and pro-migratory pathways downstream of the receptor, for instance, increases extra-cellular regulated kinase (Erk1/2), Protein kinase B (Akt) and phosphatidylinositide 3-kinase (PI3K) activity and decreases phosphatase and tensin homolog (PTEN) expression and activity. PDGFR can also heterodimerize with and transactivate the epidermal growth factor receptor (EGFR). Our overarching hypothesis was to determine whether targeting PDGFR activity effectively inhibits signaling required for medulloblastoma cell migration and invasion and whether it blocks PDGFR-induced transactivation of EGFR. To explore this we used Daoy and D556 human medulloblastoma cells which we transfected with small interfering RNA (siRNA) to PDGFRβ or treated with either Imatinib mesylate (Gleevec®) or Sunitib Malate (SUTENT®), specific inhibitors of PDGFR, to block PDGFR expression and activity, respectively. Cell migration, survival and PDGFR signaling following PDGF-BB stimulation of serum-depleted cells, with and without PDGFR inhibition, was measured. PDGF-BB treatment of cells enhanced migration and proliferation after 24 hr; increased PDGFRβ, PI3K, Akt and Erk1/2 activity, decreased PTEN activation and transactivated EGFR. Imatinib (1 uM) treatment of PDGFRβ active cells induced apoptosis at 72 hr and inhibited migration at 24 hr and invasion at 48 hr after a single dose and concomitantly inhibited PDGF-BB activation of PDGFRβ, PI3K, Akt and Erk1/2 but promoted PTEN activity. SUTENT (0.2 uM) treatment similarly inhibited short (4 hr) and long-term (24 hr) cell migration and cell invasion. PDGF-BB activation of PDGFRβ, PI3K, Akt and Erk1/2 was simultaneously inhibited by SUTENT treatment, while PTEN activity was promoted, without any affect on apoptosis. siRNA silencing of PDGFRβ similarly inhibited survival, migration and signaling and both siRNA and Imatinib or SUTENT treatment inhibited PDGF-BB-induced EGFR trans-activation. Inhibition of PDGFRβ in medulloblastoma cells by siRNA or drug treatment effectively blocked PDGFRβ signaling and EGFR transactivation and concomitantly inhibited cell migration and invasion. These results indicate that PDGFRβ tyrosine kinase activity is critical for survival and migration/invasion of medulloblastoma cells, in part by decreasing PTEN activity and transactivating EGFR, and thus may represent an important therapeutic target for this disease. en_US
dc.language.iso en en_US
dc.title Investigating the mechanism by which the platelet-derived growth factor receptor promotes metastasis in medulloblastoma en_US
dc.type Thesis en_US
dc.author.degree PHD en_US
dc.author.school SOP en_US
dc.author.idnumber 201005279 en_US
dc.author.department Pharmaceutical Sciences Department en_US
dc.description.embargo N/A en_US
dc.author.advisor MAcDonald, Tobey J.
dc.keywords Health and environmental sciences en_US
dc.keywords Biological sciences en_US
dc.keywords EGFR en_US
dc.keywords Medulloblastoma en_US
dc.keywords Metastasis en_US
dc.keywords Platelet-derived growth factor en_US
dc.identifier.ctation AbouAntoun, T. J. (2008). Investigating the mechanism by which the platelet-derived growth factor receptor promotes metastasis in medulloblastoma (Doctoral dissertation, The George Washington University). en_US
dc.author.email tamara.abouantoun@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://search.proquest.com/docview/193997870?accountid=27870 en_US
dc.publisher.institution George Washington University en_US
dc.author.affiliation Lebanese American University en_US

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