PMID- 14681687
OWN - NLM
STAT- MEDLINE
DCOM- 20040121
LR  - 20211203
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 22
IP  - 58
DP  - 2003 Dec 18
TI  - Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 
      proteins and inhibits Ewing's sarcoma cell proliferation.
PG  - 9282-7
AB  - Ewing's sarcoma (ES) is the prototype of a family of tumors (ESFT) of 
      neuroectodermal origin formed by small, round cells with limited neural 
      differentiation, which arise most frequently within bones in children or 
      adolescents. The proliferation of ESFT cells is highly dependent on the 
      establishment of, and signaling through several growth factor-mediated autocrine 
      loops. The mammalian target of rapamycin (mTOR) is a central regulator of 
      translation and cell proliferation, involved in the cellular response to various 
      nutritional, stress and mitogenic effectors. As mTOR has recently been associated 
      with certain human cancers, we investigated the possibility that mTOR played a 
      role in the regulation of ES cell proliferation. Results showed that ES cell 
      lines carrying EWS/FLI-1 alleles of different types expressed different levels of 
      total and phosphorylated mTOR protein. We demonstrate that rapamycin, an mTOR 
      inhibitor, efficiently blocked the proliferation of all cell lines by promoting 
      cell cycle arrest at the G1 phase. This was paralleled by the downregulation of 
      the levels of the EWS/FLI-1 proteins, regardless of their fusion type, and the 
      concomitant restoration of the expression of the TGF-beta type 2 receptor 
      (TGFbeta RII), which is known to be repressed by several EWS-ETS fusion proteins. 
      The expression of a rapamycin-resistant mTOR construct prevented both the 
      proliferation blockade and the EWS/FLI-1 downregulation. These data demonstrate 
      that mTOR signaling plays a central role in ES cell pathobiology and strongly 
      suggest that the use of rapamycin as a cytostatic agent may be an efficient tool 
      for the treatment of ES patients.
FAU - Mateo-Lozano, Silvia
AU  - Mateo-Lozano S
AD  - Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine, 
      Georgetown University Medical Center, Washington, DC 20057-1482, USA.
FAU - Tirado, Oscar M
AU  - Tirado OM
FAU - Notario, Vicente
AU  - Notario V
LA  - eng
GR  - P01-CA74175/CA/NCI NIH HHS/United States
GR  - P30-CA51008/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (EWS-FLI fusion protein)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (Proto-Oncogene Protein c-fli-1)
RN  - 0 (RNA-Binding Protein EWS)
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type II)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Alleles
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Apoptosis
MH  - Cell Division
MH  - Cell Line, Tumor
MH  - *Down-Regulation
MH  - G1 Phase
MH  - Humans
MH  - Oncogene Proteins, Fusion/*biosynthesis/genetics
MH  - Phosphorylation
MH  - Protein Kinases/metabolism
MH  - Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Protein c-fli-1
MH  - RNA-Binding Protein EWS
MH  - Receptor, Transforming Growth Factor-beta Type II
MH  - Receptors, Transforming Growth Factor beta/metabolism
MH  - Sarcoma, Ewing/*metabolism
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
MH  - Transcription Factors/*biosynthesis/genetics
EDAT- 2003/12/19 05:00
MHDA- 2004/01/22 05:00
CRDT- 2003/12/19 05:00
PHST- 2003/12/19 05:00 [pubmed]
PHST- 2004/01/22 05:00 [medline]
PHST- 2003/12/19 05:00 [entrez]
AID - 1207081 [pii]
AID - 10.1038/sj.onc.1207081 [doi]
PST - ppublish
SO  - Oncogene. 2003 Dec 18;22(58):9282-7. doi: 10.1038/sj.onc.1207081.