IngentaConnect TGF- receptor kinase inhibitor LY2109761 reverses the anti-apopto...

Authors: Xu, Yuanyuan¹; Tabe, Yoko; Jin, Linhua¹; Watt, Julie²; McQueen, Teresa²; Ohsaka, Akimichi³; Andreeff, Michael; Konopleva, Marina

Source: British Journal of Haematology, Volume 142, Number 2, July 2008 , pp. 192-201(10)

Publisher: Blackwell Publishing

Abstract:

Summary

Transforming growth factor β1 (TGF-β1) is an essential regulator of cell proliferation, survival and apoptosis, depending on the cellular context. TGF-β1 is also known to affect cell-to-cell interactions between tumour cells and stromal cells. We investigated the role of TGF-β1 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-β1 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-β1 were inhibited by LY2109761 or TGF-β1 neutralizing antibody. rhTGF-β1 increased pro-survival phosphorylation of Akt, which was inhibited by LY2109761. The combination of rhTGF-β1 and MSC co-culture induced significant upregulation of C/EBPβ gene (CEBPB) and protein expression along with increased C/EBPβ liver-enriched activating protein: liver-enriched inhibitory protein ratio, suggesting the novel role of C/EBPβ in TGF-β1-mediated U937 cell survival in the context of stromal cell support. In summary, these results indicate that TGF-β1 produced by BM stromal cells promotes the survival and chemoresistance of leukaemia cells under the direct cell-to-cell interactions. The blockade of TGF-β 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.

Keywords: transforming growth factor-β1; LY 2109761; mesenchymal stem cell; U937; bone marrow microenvironment

Document Type: Research article

DOI: 10.1111/j.1365-2141.2008.07130.x

Affiliations: 1: Department of Clinical Pathology, Juntendo University School of Medicine, Tokyo, Japan 2: Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA 3: Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University School of Medicine, Tokyo, Japan

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TGF-β receptor kinase inhibitor LY2109761 reverses the anti-apoptotic effects of TGF-β1 in myelo-monocytic leukaemic cells co-cultured with stromal cells