PMID- 20014066
OWN - NLM
STAT- MEDLINE
DCOM- 20100805
LR  - 20211203
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Linking)
VI  - 109
IP  - 2
DP  - 2010 Feb 1
TI  - RAD 001 (everolimus) prevents mTOR and Akt late re-activation in response to 
      imatinib in chronic myeloid leukemia.
PG  - 320-8
LID - 10.1002/jcb.22380 [doi]
AB  - The mammalian target of rapamycin (mTOR) is one target of BCR-ABL fusion gene of 
      chronic myeloid leukemia (CML). Moreover, it drives a compensatory route to 
      Imatinib mesylate (IM) possibly involved in the progression of leukemic 
      progenitors towards a drug-resistant phenotype. Accordingly, mTOR inhibitors are 
      proposed for combined therapeutic strategies in CML. The major caveat in the use 
      of mTOR inhibitors for cancer therapy comes from the induction of an 
      mTOR-phosphatidylinositol 3 kinase (PI3k) feedback loop driving the retrograde 
      activation of Akt. Here we show that the rapamycin derivative RAD 001 
      (everolimus, Novartis Institutes for Biomedical Research) inhibits mTOR and, more 
      importantly, revokes mTOR late re-activation in response to IM. RAD 001 
      interferes with the assembly of both mTOR complexes: mTORC1 and mTORC2. The 
      inhibition of mTORC2 results in the de-phosphorylation of Akt at Ser(473) in the 
      hydrophobic motif of C-terminal tail required for Akt full activation and 
      precludes Akt re-phosphorylation in response to IM. Moreover, RAD 001-induced 
      inhibition of Akt causes the de-phosphorylation of tuberous sclerosis tumor 
      suppressor protein TSC2 at 14-3-3 binding sites, TSC2 release from 14-3-3 sigma 
      (restoring its inhibitory function on mTORC1) and nuclear import (promoting the 
      nuclear translocation of cyclin-dependent kinase [CDK] inhibitor p27(Kip1), the 
      stabilization of p27(Kip1) ligand with CDK2, and the G(0)/G(1) arrest). RAD 001 
      cytotoxicity on cells not expressing the BCR-ABL fusion gene or its p210 protein 
      tyrosine kinase (TK) activity suggests that the inhibition of normal 
      hematopoiesis may represent a drug side effect.
CI  - (c) 2009 Wiley-Liss, Inc.
FAU - Mancini, Manuela
AU  - Mancini M
AD  - Dipartimento di Ematologia e Scienze Oncologiche "Lorenzo e Ariosto Seragnoli," 
      University of Bologna-Medical School, Bologna, Italy. mancini_manu@yahoo.com
FAU - Petta, Sara
AU  - Petta S
FAU - Martinelli, Giovanni
AU  - Martinelli G
FAU - Barbieri, Enza
AU  - Barbieri E
FAU - Santucci, Maria A
AU  - Santucci MA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (14-3-3 Proteins)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Crtc2 protein, mouse)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Piperazines)
RN  - 0 (Proteins)
RN  - 0 (Pyrimidines)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.- (Exonucleases)
RN  - EC 3.1.- (Exoribonucleases)
RN  - EC 3.1.- (SFN protein, human)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - 14-3-3 Proteins
MH  - Active Transport, Cell Nucleus/drug effects
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Benzamides
MH  - Biomarkers, Tumor/metabolism
MH  - Cell Line
MH  - Cell Proliferation
MH  - Drug Interactions
MH  - Drug Resistance
MH  - Everolimus
MH  - Exonucleases/metabolism
MH  - Exoribonucleases
MH  - Fusion Proteins, bcr-abl/metabolism
MH  - Hematopoiesis
MH  - Imatinib Mesylate
MH  - Intracellular Signaling Peptides and Proteins/antagonists & 
      inhibitors/*metabolism
MH  - Lethal Dose 50
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug 
      therapy/pathology/physiopathology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes
MH  - Myeloid Progenitor Cells
MH  - Neoplasm Proteins/metabolism
MH  - Phosphorylation
MH  - Piperazines/*pharmacology
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Proteins
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*metabolism
MH  - Pyrimidines/*pharmacology
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Trans-Activators/metabolism
MH  - Transcription Factors/metabolism
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/metabolism
EDAT- 2009/12/17 06:00
MHDA- 2010/08/06 06:00
CRDT- 2009/12/17 06:00
PHST- 2009/12/17 06:00 [entrez]
PHST- 2009/12/17 06:00 [pubmed]
PHST- 2010/08/06 06:00 [medline]
AID - 10.1002/jcb.22380 [doi]
PST - ppublish
SO  - J Cell Biochem. 2010 Feb 1;109(2):320-8. doi: 10.1002/jcb.22380.