PMID- 16818631
OWN - NLM
STAT- MEDLINE
DCOM- 20060907
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 13
DP  - 2006 Jul 1
TI  - Activation of mammalian target of rapamycin signaling pathway contributes to 
      tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell 
      lymphoma.
PG  - 6589-97
AB  - Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) 
      frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of 
      chimeric nucleophosmin-ALK. Previously, nucleophosmin-ALK has been shown to 
      activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the 
      serine/threonine kinase AKT. In this study, we hypothesized that the mammalian 
      target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates 
      the oncogenic effects of activated PI3K/AKT in ALK+ ALCL. Here, we provide 
      evidence that mTOR signaling phosphoproteins, including mTOR, eukaryotic 
      initiation factor 4E-binding protein-1, p70S6K, and ribosomal protein S6, are 
      highly phosphorylated in ALK+ ALCL cell lines and tumors. We also show that AKT 
      activation contributes to mTOR phosphorylation, at least in part, as forced 
      expression of constitutively active AKT by myristoylated AKT adenovirus results 
      in increased phosphorylation of mTOR and its downstream effectors. Conversely, 
      inhibition of AKT expression or activity results in decreased mTOR 
      phosphorylation. In addition, pharmacologic inhibition of PI3K/AKT down-regulates 
      the activation of the mTOR signaling pathway. We also show that inhibition of 
      mTOR with rapamycin, as well as silencing mTOR gene product expression using 
      mTOR-specific small interfering RNA, decreased phosphorylation of mTOR signaling 
      proteins and induced cell cycle arrest and apoptosis in ALK+ ALCL cells. Cell 
      cycle arrest was associated with modulation of G(1)-S-phase regulators, including 
      the cyclin-dependent kinase inhibitors p21(waf1) and p27(kip1). Apoptosis 
      following inhibition of mTOR expression or function was associated with 
      down-regulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2. 
      These findings suggest that the mTOR pathway contributes to 
      nucleophosmin-ALK/PI3K/AKT-mediated tumorigenesis and that inhibition of mTOR 
      represents a potential therapeutic strategy in ALK+ ALCL.
FAU - Vega, Francisco
AU  - Vega F
AD  - Department of Hematopathology, The University of Texas M.D. Anderson Cancer 
      Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
FAU - Medeiros, L Jeffrey
AU  - Medeiros LJ
FAU - Leventaki, Vasiliki
AU  - Leventaki V
FAU - Atwell, Coralyn
AU  - Atwell C
FAU - Cho-Vega, Jeong Hee
AU  - Cho-Vega JH
FAU - Tian, Ling
AU  - Tian L
FAU - Claret, Francois-Xavier
AU  - Claret FX
FAU - Rassidakis, George Z
AU  - Rassidakis GZ
LA  - eng
GR  - R01 CA090853/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (ALK protein, human)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Anaplastic Lymphoma Kinase
MH  - Apoptosis/drug effects/physiology
MH  - Cell Cycle/physiology
MH  - Cell Line, Tumor
MH  - Cell Survival/physiology
MH  - Chromones/pharmacology
MH  - Down-Regulation
MH  - Enzyme Activation
MH  - Humans
MH  - Lymphoma, Large B-Cell, Diffuse/enzymology/genetics/*metabolism/pathology
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein Kinases/genetics/*metabolism
MH  - Protein-Tyrosine Kinases/biosynthesis/*metabolism
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism
MH  - RNA, Small Interfering/genetics
MH  - Receptor Protein-Tyrosine Kinases
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
PMC - PMC4839264
MID - NIHMS443817
EDAT- 2006/07/05 09:00
MHDA- 2006/09/08 09:00
PMCR- 2016/04/21
CRDT- 2006/07/05 09:00
PHST- 2006/07/05 09:00 [pubmed]
PHST- 2006/09/08 09:00 [medline]
PHST- 2006/07/05 09:00 [entrez]
PHST- 2016/04/21 00:00 [pmc-release]
AID - 66/13/6589 [pii]
AID - 10.1158/0008-5472.CAN-05-3018 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Jul 1;66(13):6589-97. doi: 10.1158/0008-5472.CAN-05-3018.