Journal of Neuro-Oncology

, Volume 71, Issue 3, pp 215–222

PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas

  • Jean L. Nakamura
  • Amelia Karlsson
  • Nils D. Arvold
  • Alexander R. Gottschalk
  • Russell O. Pieper
  • David Stokoe
  • Daphne A. Haas-Kogan
Laboratory Investigation


The phosphoinositide 3-kinase (PI3-kinase) signaling pathway is frequently aberrantly activated in glioblastoma multiforme (GM) by mutation or loss of the 3′ phospholipid phosphatase PTEN. PTEN abnormalities result in inappropriate signaling to downstream molecules including protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR). PI3-kinase activation increases resistance to radiation-induced cell death; conversely, PI3-kinase inhibition enhances the sensitivity of tumors to radiation. The effects of LY294002, a biochemical inhibitor of PI3-kinase, on the response to radiation were examined in the PTEN mutant glioma cell line U251 MG. Low doses of LY294002 sensitized U251 MG to clinically relevant doses of radiation. In contrast to LY294002, rapamycin, an inhibitor of mTOR, did not result in radiosensitization. We demonstrate that among multiple known targets of LY294002, PI3-kinase is the most likely molecule responsible for LY294002-induced radiosensitization. Furthermore, using a myristoylated PKB/Akt construct, we identified PKB/Akt as the downstream molecule that mediates the synergistic cytotoxicity between LY294002 and radiation. Thus PI3-kinase dysregulation may contribute to the notable radioresistance of GM tumors and inhibition of PKB/Akt offers an excellent target to enhance radiosensitivity.


glioma LY294002 phosphatidylinositol 3-kinase radiation signal transduction 



glioblastoma multiforme


phosphatidylinositol 3-kinase


protein kinase B


phosphatase and tensin homologue deleted on chromosome ten


standard error of the mean


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Copyright information

© Springer 2005

Authors and Affiliations

  • Jean L. Nakamura
    • 1
  • Amelia Karlsson
    • 1
  • Nils D. Arvold
    • 1
  • Alexander R. Gottschalk
    • 1
  • Russell O. Pieper
    • 2
  • David Stokoe
    • 2
    • 3
  • Daphne A. Haas-Kogan
    • 1
    • 2
    • 4
  1. 1.Departments of Radiation OncologyThe University of CaliforniaUSA
  2. 2.Brain Tumor Research Center and NeurosurgeryThe University of CaliforniaUSA
  3. 3.Cancer Research CenterThe University of CaliforniaSan FranciscoUSA
  4. 4.Department of Radiation Oncology and Comprehensive Cancer CenterUCSFSan FranciscoUSA

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