PMID- 22843885
OWN - NLM
STAT- MEDLINE
DCOM- 20121015
LR  - 20211203
IS  - 1791-7530 (Electronic)
IS  - 0250-7005 (Linking)
VI  - 32
IP  - 8
DP  - 2012 Aug
TI  - PI3K/mTOR signaling pathways in medulloblastoma.
PG  - 3141-6
AB  - Medulloblastoma is the most common malignant brain tumor in children. Recent 
      studies have implicated sonic hedgehog (SHH) and insulin growth factor (IGF) as 
      important mediators in deregulated pathways, which directly inactivate tuberous 
      sclerosis complex, leading to activation of the serine/threonine kinase, 
      mammalian target of rapamycin (mTOR). mTOR consists of two catalytic subunits of 
      biochemically distinct complexes called mTORC1 and mTORC2. This study aims to 
      further elucidate the role of the mTOR pathway, in the development of 
      medulloblastoma, and assess the use of mTOR inhibitors as novel therapeutic 
      agents. Medulloblastoma cells treated with mTORC1 inhibitor, rapamycin, 
      down-regulated pERK expression initially; however ERK activation was evident upon 
      prolonged treatment. Phosphorylation of mTORC1 substrate, p70S6K at thr389 was 
      reduced by rapamycin and pretreatment with rapamycin abrogated platelet-derived 
      growth factor (PDGF)-induced activation of S6K, as well as that of mTORC2 
      substrate pAKT(Ser473). Activation of AKT was decreased at 1, 3, and 6 h of 
      treatment, but extended treatment with rapamycin increased expression of 
      pAKT(Ser473). Expression of cyclic dependent kinase inhibitor, P27, decreased 
      following PDGF and increased following rapamycin treatment, suggesting their 
      respective impact on cell proliferation via cell cycle control. Cell 
      proliferation was increased by 12-O-tetradecanoylphorbol-13-acetate (TPA) 
      treatment of medulloblastoma cells, while it was suppressed following treatment 
      with rapamycin or U0126 (MEK1/2 inhibitor). pp242, a novel combined mTORC1/2 
      inhibitor, and rapamycin limited proliferation by reducing the S-Phase entry as 
      assessed by EdU incorporation, while PDGF increased EdU incorporation. pp242 
      reduced the number of cells entering the S-phase to a greater extent than did 
      rapamycin. Migration of medulloblastoma cells towards fibronectin was suppressed 
      in a time-dependent manner after rapamycin treatment. These results indicate that 
      the mTOR pathway is involved in the pathogenesis of medulloblastoma, and that 
      targeting this pathway may provide a strategy for therapy of medulloblastoma.
FAU - Mohan, Avinash L
AU  - Mohan AL
AD  - Department of Neurosurgery, New York Medical College, Valhalla, NY, USA.
FAU - Friedman, Marissa D
AU  - Friedman MD
FAU - Ormond, D Ryan
AU  - Ormond DR
FAU - Tobias, Michael
AU  - Tobias M
FAU - Murali, Raj
AU  - Murali R
FAU - Jhanwar-Uniyal, Meena
AU  - Jhanwar-Uniyal M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Greece
TA  - Anticancer Res
JT  - Anticancer research
JID - 8102988
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cerebellar Neoplasms/*enzymology/pathology
MH  - Enzyme Activation
MH  - Fluorescent Antibody Technique
MH  - Humans
MH  - Medulloblastoma/*enzymology/pathology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
EDAT- 2012/07/31 06:00
MHDA- 2012/10/16 06:00
CRDT- 2012/07/31 06:00
PHST- 2012/07/31 06:00 [entrez]
PHST- 2012/07/31 06:00 [pubmed]
PHST- 2012/10/16 06:00 [medline]
AID - 32/8/3141 [pii]
PST - ppublish
SO  - Anticancer Res. 2012 Aug;32(8):3141-6.