PMID- 20080710
OWN - NLM
STAT- MEDLINE
DCOM- 20100312
LR  - 20211203
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 4
DP  - 2010 Jan 26
TI  - Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent 
      type I IFN production.
PG  - 1576-81
LID - 10.1073/pnas.0912344107 [doi]
AB  - Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). 
      However, virus-induced type I IFN greatly limits its clinical application. The 
      kinase mammalian target of rapamycin (mTOR) stimulates type I IFN production via 
      phosphorylation of its effector proteins, 4E-BPs and S6Ks. Here we show that 
      mouse embryonic fibroblasts and mice lacking S6K1 and S6K2 are more susceptible 
      to vesicular stomatitis virus (VSV) infection than their WT counterparts as a 
      result of an impaired type I IFN response. We used this knowledge to employ a 
      pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR 
      rapamycin, in combination with an IFN-sensitive VSV-mutant strain 
      (VSV(DeltaM51)), dramatically increased the survival of immunocompetent rats 
      bearing MGs. More importantly, VSV(DeltaM51) selectively killed tumor, but not 
      normal cells, in MG-bearing rats treated with rapamycin. These results 
      demonstrate that reducing type I IFNs through inhibition of mTORC1 is an 
      effective strategy to augment the therapeutic activity of VSV(DeltaM51).
FAU - Alain, Tommy
AU  - Alain T
AD  - Department of Biochemistry and Goodman Cancer Center, McGill University, 
      Montreal, QC H3G 1Y6, Canada.
FAU - Lun, XueQing
AU  - Lun X
FAU - Martineau, Yvan
AU  - Martineau Y
FAU - Sean, Polen
AU  - Sean P
FAU - Pulendran, Bali
AU  - Pulendran B
FAU - Petroulakis, Emmanuel
AU  - Petroulakis E
FAU - Zemp, Franz J
AU  - Zemp FJ
FAU - Lemay, Chantal G
AU  - Lemay CG
FAU - Roy, Dominic
AU  - Roy D
FAU - Bell, John C
AU  - Bell JC
FAU - Thomas, George
AU  - Thomas G
FAU - Kozma, Sara C
AU  - Kozma SC
FAU - Forsyth, Peter A
AU  - Forsyth PA
FAU - Costa-Mattioli, Mauro
AU  - Costa-Mattioli M
FAU - Sonenberg, Nahum
AU  - Sonenberg N
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100104
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Interferon Type I)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (Rps6ka1 protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Female
MH  - Glioma/genetics/*metabolism/*therapy/virology
MH  - Interferon Type I/*biosynthesis
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Knockout
MH  - Multiprotein Complexes
MH  - Neoplasm Transplantation
MH  - Oncolytic Virotherapy
MH  - Proteins
MH  - Rats
MH  - Rats, Inbred F344
MH  - Ribosomal Protein S6 Kinases/deficiency/metabolism
MH  - Ribosomal Protein S6 Kinases, 90-kDa/deficiency/metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/*metabolism
MH  - Vesicular Stomatitis/genetics/*metabolism/virology
MH  - Vesiculovirus/genetics/*physiology
PMC - PMC2824402
COIS- The authors declare no conflict of interest.
EDAT- 2010/01/19 06:00
MHDA- 2010/03/13 06:00
PMCR- 2010/07/26
CRDT- 2010/01/19 06:00
PHST- 2010/01/19 06:00 [entrez]
PHST- 2010/01/19 06:00 [pubmed]
PHST- 2010/03/13 06:00 [medline]
PHST- 2010/07/26 00:00 [pmc-release]
AID - 0912344107 [pii]
AID - 200912344 [pii]
AID - 10.1073/pnas.0912344107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1576-81. doi: 
      10.1073/pnas.0912344107. Epub 2010 Jan 4.