PMID- 16199861
OWN - NLM
STAT- MEDLINE
DCOM- 20051121
LR  - 20220331
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 25
IP  - 20
DP  - 2005 Oct
TI  - mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme 
      cells.
PG  - 8809-23
AB  - The tumor-selective, proapoptotic, death receptor ligand tumor necrosis 
      factor-related apoptosis-inducing ligand (TRAIL) is a mediator of antitumor drug 
      activity and in itself is a promising agent for the treatment of human 
      malignancies. Like many tumors, however, glioblastoma multiforme (GBM), the most 
      fatal form of glioma, exhibits a range of TRAIL sensitivity, and only a small 
      percentage of GBM tumors undergo TRAIL-induced apoptosis. We here show that TRAIL 
      resistance in GBM is a consequence of overexpression of the short isoform of the 
      caspase-8 inhibitor, c-FLICE inhibitory protein (FLIP(S)), and that FLIP(S) 
      expression is in turn translationally enhanced by activation of the Akt-mammalian 
      target of rapamycin (mTOR)-p70 S6 kinase 1 (S6K1) pathway. Conversely, 
      pharmacologic or genetic inhibition of mTOR, or the mTOR target S6K1, suppresses 
      polyribosomal accumulation of FLIP(S) mRNA, FLIP(S) protein expression, and TRAIL 
      resistance. In archived material from 12 human GBM tumors, PTEN status was a 
      predictor of activation of the Akt-mTOR-S6K1 pathway and of FLIP(S) levels, while 
      in xenografted human GBM, activation status of the PTEN-Akt-mTOR pathway 
      distinguished the tumors inherently sensitive to TRAIL from those which could be 
      sensitized by the mTOR inhibitor rapamycin. These results define the mTOR pathway 
      as a key limiter of tumor elimination by TRAIL-mediated mechanisms, provide a 
      means by which the TRAIL-sensitive subset of GBM can be identified, and provide 
      rationale for the combined use of TRAIL with mTOR inhibitors in the treatment of 
      human cancers.
FAU - Panner, Amith
AU  - Panner A
AD  - Brain Tumor Research Center, Department of Neurological Surgery, University of 
      California San Francisco, 94143-0875, USA.
FAU - James, C David
AU  - James CD
FAU - Berger, Mitchel S
AU  - Berger MS
FAU - Pieper, Russell O
AU  - Pieper RO
LA  - eng
GR  - P50 CA097257/CA/NCI NIH HHS/United States
GR  - R01 CA094989/CA/NCI NIH HHS/United States
GR  - P50 CA97257/CA/NCI NIH HHS/United States
GR  - R01 CA94989/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (CFLAR protein, human)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFSF10 protein, human)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Apoptosis Regulatory Proteins/*pharmacology
MH  - Base Sequence
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein
MH  - Cell Line, Tumor
MH  - DNA, Neoplasm/genetics
MH  - Drug Resistance, Neoplasm
MH  - Gene Expression
MH  - Glioblastoma/drug therapy/*genetics/*metabolism
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*genetics
MH  - Membrane Glycoproteins/*pharmacology
MH  - PTEN Phosphohydrolase/metabolism
MH  - Protein Biosynthesis
MH  - Protein Kinases/genetics/*metabolism
MH  - Recombinant Proteins/pharmacology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/genetics/metabolism
MH  - TNF-Related Apoptosis-Inducing Ligand
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Necrosis Factor-alpha/*pharmacology
PMC - PMC1265779
EDAT- 2005/10/04 09:00
MHDA- 2005/12/13 09:00
PMCR- 2005/10/01
CRDT- 2005/10/04 09:00
PHST- 2005/10/04 09:00 [pubmed]
PHST- 2005/12/13 09:00 [medline]
PHST- 2005/10/04 09:00 [entrez]
PHST- 2005/10/01 00:00 [pmc-release]
AID - 25/20/8809 [pii]
AID - 0712-05 [pii]
AID - 10.1128/MCB.25.20.8809-8823.2005 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2005 Oct;25(20):8809-23. doi: 10.1128/MCB.25.20.8809-8823.2005.