Document Detail

TGF-beta receptor kinase inhibitor LY2109761 reverses the anti-apoptotic effects of TGF-beta1 in myelo-monocytic leukaemic cells co-cultured with stromal cells.
MedLine Citation:
PMID:  18492113     Owner:  NLM     Status:  MEDLINE    
Transforming growth factor beta1 (TGF-beta1) is an essential regulator of cell proliferation, survival and apoptosis, depending on the cellular context. TGF-beta1 is also known to affect cell-to-cell interactions between tumour cells and stromal cells. We investigated the role of TGF-beta1 in the survival of myelo-monocytic leukaemia cell lines co-cultured with bone marrow (BM)-derived mesenchymal stem cells (MSC). Treatment with recombinant human (rh)TGF-beta1 inhibited spontaneous and cytarabine-induced apoptosis in U937 cells, most prominently in U937 cells directly attached to MSCs. Conversely, the pro-survival effects of TGF-beta1 were inhibited by LY2109761 or TGF-beta1 neutralizing antibody. rhTGF-beta1 increased pro-survival phosphorylation of Akt, which was inhibited by LY2109761. The combination of rhTGF-beta1 and MSC co-culture induced significant upregulation of C/EBPbeta gene (CEBPB) and protein expression along with increased C/EBPbeta liver-enriched activating protein: liver-enriched inhibitory protein ratio, suggesting the novel role of C/EBPbeta in TGF-beta1-mediated U937 cell survival in the context of stromal cell support. In summary, these results indicate that TGF-beta1 produced by BM stromal cells promotes the survival and chemoresistance of leukaemia cells under the direct cell-to-cell interactions. The blockade of TGF-beta signalling by LY2109761, which effectively inhibited the pro-survival signalling, may enhance the efficacy of chemotherapy against myelo-monocytic leukaemic cells in the BM microenvironment.
Yuanyuan Xu; Yoko Tabe; Linhua Jin; Julie Watt; Teresa McQueen; Akimichi Ohsaka; Michael Andreeff; Marina Konopleva
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-05-19
Journal Detail:
Title:  British journal of haematology     Volume:  142     ISSN:  1365-2141     ISO Abbreviation:  Br. J. Haematol.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2009-09-15     Completed Date:  2010-02-22     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  0372544     Medline TA:  Br J Haematol     Country:  England    
Other Details:
Languages:  eng     Pagination:  192-201     Citation Subset:  IM    
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MeSH Terms
Antigens, CD14 / metabolism
Apoptosis / drug effects*
Blotting, Western
Cell Cycle / drug effects
Cell Line, Tumor / metabolism
Cells, Cultured / drug effects
Coculture Techniques
Enzyme Inhibitors / pharmacology*
Leukemia / drug therapy*,  metabolism
Mesenchymal Stromal Cells / metabolism
Pyrazoles / pharmacology*
Pyrroles / pharmacology*
Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
Stromal Cells / metabolism
Transforming Growth Factor beta1 / pharmacology*,  secretion
U937 Cells / metabolism
Grant Support
Reg. No./Substance:
0/Antigens, CD14; 0/Enzyme Inhibitors; 0/LY2109761; 0/Pyrazoles; 0/Pyrroles; 0/Receptors, Transforming Growth Factor beta; 0/Transforming Growth Factor beta1

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