PMID- 20668229
OWN - NLM
STAT- MEDLINE
DCOM- 20101221
LR  - 20211203
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 116
IP  - 20
DP  - 2010 Nov 18
TI  - The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid 
      leukemia through the repression of mTOR-dependent oncogenic mRNA translation.
PG  - 4262-73
LID - 10.1182/blood-2010-02-269837 [doi]
AB  - Finding an effective treatment for acute myeloid leukemia (AML) remains a 
      challenge, and all cellular processes that are deregulated in AML cells should be 
      considered in the design of targeted therapies. We show in our current study that 
      the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated 
      by the biguanide molecule metformin, resulting in a specific inhibition of 
      mammalian target of rapamycin (mTOR) catalytic activity. This induces a multisite 
      dephosphorylation of the key translation regulator, 4E-BP1, which markedly 
      inhibits the initiation step of mRNA translation. Consequently, metformin reduces 
      the recruitment of mRNA molecules encoding oncogenic proteins to the polysomes, 
      resulting in a strong antileukemic activity against primary AML cells while 
      sparing normal hematopoiesis ex vivo and significantly reducing the growth of AML 
      cells in nude mice. The induction of the LKB1/AMPK tumor-suppressor pathway thus 
      represents a promising new strategy for AML therapy.
FAU - Green, Alexa S
AU  - Green AS
AD  - Institut Cochin, Universite Paris Descartes, CNRS (UMR8104), Paris, France.
FAU - Chapuis, Nicolas
AU  - Chapuis N
FAU - Maciel, Thiago Trovati
AU  - Maciel TT
FAU - Willems, Lise
AU  - Willems L
FAU - Lambert, Mireille
AU  - Lambert M
FAU - Arnoult, Christophe
AU  - Arnoult C
FAU - Boyer, Olivier
AU  - Boyer O
FAU - Bardet, Valerie
AU  - Bardet V
FAU - Park, Sophie
AU  - Park S
FAU - Foretz, Marc
AU  - Foretz M
FAU - Viollet, Benoit
AU  - Viollet B
FAU - Ifrah, Norbert
AU  - Ifrah N
FAU - Dreyfus, Francois
AU  - Dreyfus F
FAU - Hermine, Olivier
AU  - Hermine O
FAU - Moura, Ivan Cruz
AU  - Moura IC
FAU - Lacombe, Catherine
AU  - Lacombe C
FAU - Mayeux, Patrick
AU  - Mayeux P
FAU - Bouscary, Didier
AU  - Bouscary D
FAU - Tamburini, Jerome
AU  - Tamburini J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100728
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (STK11 protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Biocatalysis/drug effects
MH  - Cell Cycle Proteins
MH  - Cell Death/drug effects
MH  - Cell Proliferation/drug effects
MH  - Enzyme Activation/drug effects
MH  - Hematopoietic Stem Cells/cytology/drug effects/metabolism
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*enzymology/genetics/pathology
MH  - Metformin/pharmacology
MH  - Mice
MH  - Neoplasm Proteins/*biosynthesis
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation/drug effects
MH  - Polyribosomes/drug effects/metabolism
MH  - *Protein Biosynthesis/drug effects
MH  - Protein Kinases/*metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - *Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/metabolism
EDAT- 2010/07/30 06:00
MHDA- 2010/12/22 06:00
CRDT- 2010/07/30 06:00
PHST- 2010/07/30 06:00 [entrez]
PHST- 2010/07/30 06:00 [pubmed]
PHST- 2010/12/22 06:00 [medline]
AID - S0006-4971(20)31066-1 [pii]
AID - 10.1182/blood-2010-02-269837 [doi]
PST - ppublish
SO  - Blood. 2010 Nov 18;116(20):4262-73. doi: 10.1182/blood-2010-02-269837. Epub 2010 
      Jul 28.