TGF-beta receptor kinase inhibitor LY2109761 reverses the anti-apoptotic effects of TGF-beta1 in myelo-monocytic leukaemic cells co-cultured with stromal cells.
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.
Xu
Yuanyuan
Y
Department of Clinical Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Tabe
Yoko
Y
Jin
Linhua
L
Watt
Julie
J
McQueen
Teresa
T
Ohsaka
Akimichi
A
Andreeff
Michael
M
Konopleva
Marina
M
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D017154:Stromal Cells / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*; D020298:U937 Cells / Q000378:metabolism
D004791:Enzyme Inhibitors; C530108:LY2109761; D018950:Lipopolysaccharide Receptors; D011720:Pyrazoles; D011758:Pyrroles; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1