Laboratory Investigation

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. NakamuraAffiliated withDepartments of Radiation Oncology, The University of California
  • , Amelia KarlssonAffiliated withDepartments of Radiation Oncology, The University of California
  • , Nils D. ArvoldAffiliated withDepartments of Radiation Oncology, The University of California
  • , Alexander R. GottschalkAffiliated withDepartments of Radiation Oncology, The University of California
  • , Russell O. PieperAffiliated withBrain Tumor Research Center and Neurosurgery, The University of California
  • , David StokoeAffiliated withBrain Tumor Research Center and Neurosurgery, The University of CaliforniaCancer Research Center, The University of California
  • , Daphne A. Haas-KoganAffiliated withDepartments of Radiation Oncology, The University of CaliforniaBrain Tumor Research Center and Neurosurgery, The University of CaliforniaDepartment of Radiation Oncology and Comprehensive Cancer Center, UCSF Email author 

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Abstract

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.

Keywords

glioma LY294002 phosphatidylinositol 3-kinase radiation signal transduction