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[Cancer Research 62, 6764-6769, November 15, 2002]
© 2002 American Association for Cancer Research

Tumor Biology

Mutant Epidermal Growth Factor Receptor Signaling Down-Regulates p27 through Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway in Glioblastomas1

Yoshitaka Narita, Motoo Nagane, Kazuhiko Mishima, H-J. Su Huang, Frank B. Furnari2 and Webster K. Cavenee

Ludwig Institute for Cancer Research, San Diego Branch [Y. N., H-J. S. H., F. B. F., W. K. C.]; Department of Medicine [F. B. F., W. K. C.], Center for Molecular Genetics [W. K. C.], and Cancer Center [F. B. F., W. K. C.], University of California at San Diego, La Jolla, California 92093-0660; Department of Neurosurgery, Kyorin University, Mitaka, Tokyo, 181-0004 Japan [M. N.]; and Department of Neurosurgery, Saitama Medical School, Moroyamacho, Iruma, 350-0451 Japan [K. M.]

Alterations of the epidermal growth factor receptor (EGFR) gene are common in some forms of cancer and the most frequent is a deletion of exons 2–7. We have previously shown that this mutant receptor, called {Delta}EGFR, confers enhanced tumorigenicity to glioblastoma cells through elevated proliferation and reduced apoptotic rates of the tumor cells in vivo. To understand the molecular mechanisms that underlie {Delta}EGFR-enhanced proliferation, we examined the gene products that control cell cycle progression. We found that levels of the cyclin-dependent kinase (CDK) inhibitor, p27, were lower in U87MG.{Delta}EGFR tumors than in parental U87MG or control U87MG.DK tumors. Consequently, CDK2-cyclin A activity was also elevated, concomitant with the RB protein hyperphosphorylation. In addition, activated phosphatidylinositol 3-kinase (PI3-K) and phosphorylated Akt levels were also elevated in the U87MG.{Delta}EGFR tumors. U87MG.{Delta}EGFR cells failed to arrest in G1 in response to serum starvation in vitro and while maintaining high levels of PI3-K activity and hyperphosphorylated RB. Treatment of U87MG.{Delta}EGFR cells with LY294002, a PI3-K inhibitor, caused reduced levels of phosphorylated Akt and concomitantly up-regulated levels of p27. Expression of a kinase dead dominant-negative Akt mutant in the U87MG.{Delta}EGFR cells similarly resulted in up-regulation of p27 and down-regulation of tumorigenicity in vivo. These results suggest that the constitutively active {Delta}EGFR can enhance cell proliferation in part by down-regulation of p27 through activation of the PI3-K/Akt pathway. This pathway may represent another therapeutic target for treatment of those aggressive glioblastomas expressing {Delta}EGFR.




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Copyright © 2002 by the American Association for Cancer Research.