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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Analysis of Variance
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Antibiotics, Antineoplastic / pharmacology
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Brain Neoplasms / enzymology*
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Brain Neoplasms / genetics
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Brain Neoplasms / radiotherapy
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Cell Line, Tumor
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Chromones / pharmacology*
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Down-Regulation
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / radiation effects
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Glioblastoma / enzymology*
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Glioblastoma / genetics
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Glioblastoma / radiotherapy
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Humans
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Morpholines / pharmacology*
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Mutation
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / drug effects*
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Phosphoric Monoester Hydrolases / genetics
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Protein Kinases / drug effects
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Protein Serine-Threonine Kinases / drug effects
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Protein-Tyrosine Kinases / drug effects*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins c-akt
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Radiation-Sensitizing Agents / pharmacology*
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Signal Transduction / drug effects*
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Tumor Suppressor Proteins / drug effects*
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Tumor Suppressor Proteins / genetics
Substances
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Antibiotics, Antineoplastic
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Chromones
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Enzyme Inhibitors
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Radiation-Sensitizing Agents
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Tumor Suppressor Proteins
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Protein Kinases
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MTOR protein, human
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human
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Sirolimus