Inhibition of phosphatidylinositol 3‐kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells

• Published in: International journal of cancer Vol. 105; no. 3; pp. 331 - 339
• Main Authors: Klingler‐Hoffmann, Manuela, Bukczynska, Patricia, Tiganis, Tony
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 20-06-2003; Wiley-Liss
• Subjects: Agar - pharmacology; Androstadienes - pharmacology; Animals; Biological and medical sciences; Blotting, Western; Cell Cycle; Cell Division; Cell Separation; Dogs; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors - pharmacology; ErbB Receptors - genetics; Flavonoids - pharmacology; Flow Cytometry; G1 Phase; Glioblastoma - etiology; Glioblastoma - metabolism; Humans; MAP Kinase Signaling System; Medical sciences; Mutation; Neurology; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; PI3K; PTEN; PTEN Phosphohydrolase; S Phase; Signal Transduction; Time Factors; Tumor Cells, Cultured; Tumor Suppressor Proteins - metabolism; Tumors of the nervous system. Phacomatoses; Wortmannin; ΔEGFR; Human; Nervous system diseases; Enzyme; Transferases; Cytokine; Glioblastoma; Malignant tumor; Carcinogenesis; 1-Phosphatidylinositol 3-kinase; Malignant glioma; Growth factor receptor; Epidermal growth factor; Gene; Polypeptide; Central nervous system disease; Established cell line; Genetics; Mutation; Growth factor; Tumor suppressor gene; Biological receptor
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.11085

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 ΔEGFR. ΔEGFR 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, ΔEGFR 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 ΔEGFR 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 ΔEGFR may contribute to glioblastoma development. © 2003 Wiley‐Liss, Inc.