PMID- 17001313
OWN - NLM
STAT- MEDLINE
DCOM- 20070424
LR  - 20211203
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 26
IP  - 13
DP  - 2007 Mar 22
TI  - Silencing mammalian target of rapamycin signaling by small interfering RNA 
      enhances rapamycin-induced autophagy in malignant glioma cells.
PG  - 1840-51
AB  - The mammalian target of rapamycin (mTOR) plays a central role in regulating the 
      proliferation of malignant glioma cells, and mTOR-specific inhibitors such as 
      rapamycin analogs are considered as promising therapy for malignant gliomas. 
      However, the efficacy of mTOR inhibitors alone in the treatment of patients with 
      malignant gliomas is only modest, potentially because these agents rather than 
      acting as mTOR kinase inhibitors instead interfere with the function of only 
      mTOR/raptor (regulatory-associated protein of mTOR) complex and thus do not 
      perturb all mTOR functions. The purpose of this study was to determine whether 
      global inhibition of the mTOR molecule enhances the antitumor effect of rapamycin 
      on malignant glioma cells. We showed that rapamycin induced autophagy and that 
      inhibition of autophagy by small interfering RNA (siRNA) directed against 
      autophagy-related gene Beclin 1 attenuated the cytotoxicity of rapamycin in 
      rapamycin-sensitive tumor cells, indicating that the autophagy was a primary 
      mediator of rapamycin's antitumor effect rather than a protective response. 
      Exogenous expression of an mTOR mutant interfering with its kinase activity 
      markedly enhanced the incidence of rapamycin-induced autophagy. Moreover, 
      silencing of mTOR with siRNA augmented the inhibitory effect of rapamycin on 
      tumor cell viability by stimulating autophagy. Importantly, not only 
      rapamycin-sensitive malignant glioma cells with PTEN mutations but also 
      rapamycin-resistant malignant glioma cells with wild-type PTEN were sensitized to 
      rapamycin by mTOR siRNA. These results indicate that rapamycin-induced autophagy 
      is one of the agent's antitumor effects and that silencing or inhibiting mTOR 
      kinase activity could enhance the effectiveness of rapamycin.
FAU - Iwamaru, A
AU  - Iwamaru A
AD  - Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 
      Houston, TX 77030, USA.
FAU - Kondo, Y
AU  - Kondo Y
FAU - Iwado, E
AU  - Iwado E
FAU - Aoki, H
AU  - Aoki H
FAU - Fujiwara, K
AU  - Fujiwara K
FAU - Yokoyama, T
AU  - Yokoyama T
FAU - Mills, G B
AU  - Mills GB
FAU - Kondo, S
AU  - Kondo S
LA  - eng
GR  - CA 088936/CA/NCI NIH HHS/United States
GR  - CA 108558/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060925
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Autophagy/*drug effects
MH  - Base Sequence
MH  - Brain Neoplasms/*epidemiology
MH  - Catalysis
MH  - Cell Line, Tumor
MH  - *Gene Silencing
MH  - Glioma/*genetics/pathology
MH  - Humans
MH  - Microscopy, Electron
MH  - PTEN Phosphohydrolase/metabolism
MH  - Protein Kinases/*genetics
MH  - *RNA, Small Interfering
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2006/09/27 09:00
MHDA- 2007/04/25 09:00
CRDT- 2006/09/27 09:00
PHST- 2006/09/27 09:00 [pubmed]
PHST- 2007/04/25 09:00 [medline]
PHST- 2006/09/27 09:00 [entrez]
AID - 1209992 [pii]
AID - 10.1038/sj.onc.1209992 [doi]
PST - ppublish
SO  - Oncogene. 2007 Mar 22;26(13):1840-51. doi: 10.1038/sj.onc.1209992. Epub 2006 Sep 
      25.