title: Inhibition of phosphatidylinositol 3-kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells.
abstract: In de novo glioblastoma multiforme, loss of the tumour suppressor protein PTEN can coincide with the expression of a naturally occurring mutant epidermal growth factor receptor known as deltaEGFR. DeltaEGFR signals constitutively via the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt and mitogen-activated protein kinase pathways. In human U87MG glioblastoma cells that lack PTEN, deltaEGFR expression enhances tumourigenicity by increasing cellular proliferation. Inhibition of PI3K signaling with the pharmacologic inhibitor wortmannin, or by the reconstitution of physiological levels of PTEN to dephosphorylate the lipid products of PI3K, negated the growth advantage imparted by deltaEGFR on U87MG cells. PTEN reconstitution suppressed the elevated PI3K signaling, without affecting mitogen-activated protein kinase signaling and caused a delay in G1 cell cycle progression that was concomitant with increased cyclin-dependent protein kinase inhibitor p21CIP1/WAF1 protein levels. Our study provides insight into the mechanism by which deltaEGFR may contribute to glioblastoma development.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
authors.forename: Manuela
authors.initials: M
authors.lastname: Klingler-Hoffmann
authors.forename: Patricia
authors.initials: P
authors.lastname: Bukczynska
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
mesh_terms: D000362:Agar / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D002469:Cell Separation; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics*; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase; D005909:Glioblastoma / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D009154:Mutation; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D016196:S Phase; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000362:Agar; D000730:Androstadienes; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D005419:Flavonoids; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin; C494929:PTEN protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one