PMID- 15735908
OWN - NLM
STAT- MEDLINE
DCOM- 20050707
LR  - 20211203
IS  - 0167-594X (Print)
IS  - 0167-594X (Linking)
VI  - 71
IP  - 3
DP  - 2005 Feb
TI  - PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human 
      malignant gliomas.
PG  - 215-22
AB  - 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.
FAU - Nakamura, Jean L
AU  - Nakamura JL
AD  - Department of Radiation Oncology, The University of California, San Francisco, CA 
      94143, USA.
FAU - Karlsson, Amelia
AU  - Karlsson A
FAU - Arvold, Nils D
AU  - Arvold ND
FAU - Gottschalk, Alexander R
AU  - Gottschalk AR
FAU - Pieper, Russell O
AU  - Pieper RO
FAU - Stokoe, David
AU  - Stokoe D
FAU - Haas-Kogan, Daphne A
AU  - Haas-Kogan DA
LA  - eng
GR  - P01 NS42927/NS/NINDS NIH HHS/United States
GR  - P50 CA97257/CA/NCI NIH HHS/United States
GR  - R01 CA79548/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Neurooncol
JT  - Journal of neuro-oncology
JID - 8309335
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Agammaglobulinaemia Tyrosine Kinase
MH  - Analysis of Variance
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Brain Neoplasms/*enzymology/genetics/radiotherapy
MH  - Cell Line, Tumor
MH  - Chromones/*pharmacology
MH  - Down-Regulation
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression Regulation, Neoplastic/drug effects/radiation effects
MH  - Glioblastoma/*enzymology/genetics/radiotherapy
MH  - Humans
MH  - Morpholines/*pharmacology
MH  - Mutation
MH  - PTEN Phosphohydrolase
MH  - Phosphatidylinositol 3-Kinases/drug effects
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphoric Monoester Hydrolases/*drug effects/genetics
MH  - Protein Kinases/drug effects
MH  - Protein Serine-Threonine Kinases/drug effects
MH  - Protein-Tyrosine Kinases/*drug effects
MH  - Proto-Oncogene Proteins/drug effects
MH  - Proto-Oncogene Proteins c-akt
MH  - Radiation-Sensitizing Agents/*pharmacology
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Suppressor Proteins/*drug effects/genetics
EDAT- 2005/03/01 09:00
MHDA- 2005/07/08 09:00
CRDT- 2005/03/01 09:00
PHST- 2005/03/01 09:00 [pubmed]
PHST- 2005/07/08 09:00 [medline]
PHST- 2005/03/01 09:00 [entrez]
AID - 10.1007/s11060-004-1718-y [doi]
PST - ppublish
SO  - J Neurooncol. 2005 Feb;71(3):215-22. doi: 10.1007/s11060-004-1718-y.