Abstract
The ability of death-inducing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to selectively kill a variety of cancer cells has been largely described, but one of the major concerns with the treatment is the occurrence of drug resistance and possible toxic side effects. Here, we report that TRAIL induces apoptosis in Jurkat and SUPT1 T cell lines and in human T-ALL blasts but not in healthy subject-derived peripheral blood mononuclear cells. In parallel, the treatment with TRAIL and Tyrphostin (AG-490), a selective Janus kinase 2 inhibitor, produces an evident enhancement of cytotoxicity, characterized by a significant inhibition of Stat3 phosphorylation compared to controls or to TRAIL alone-treated samples, and associated with a dramatic decrease of both cIAP-1 and cIAP-2 mRNA levels. Downregulation of cIAP-1 and cIAP-2 by specific small interference RNAs significantly amplifies TRAIL-reduced cytotoxicity. All together, these findings strongly indicate that cIAP-1 and cIAP-2 downregulation is a fundamental step in the signaling pathways mediating the combinatorial effect of TRAIL and AG-490 on T cell leukemia. These findings may help to open new routes for the development of less toxic pharmacological strategies in the treatment of patients affected by TRAIL-sensitive leukemias.
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Acknowledgements
This work was supported by Italian MIUR-COFIN 2007 funds, by Fondazione Carichieti, Chieti, Italy and by a generous donation of Marco Romanelli and Donatella De Sanctis on the day of their wedding. The authors wish to thank Prof John C Byrd (The Ohio State University, USA) for his critical review of the manuscript.
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Supplementary information, Figure S1
Flow cytometry analysis of surface expression of TRAIL receptors in Jurkat cells. (PDF 125 kb)
Supplementary information, Figure S2
Flow cytometry analysis of apoptosis in Jurkat cells after the treatment with STA-21, TRAIL or with the agonists combined together. (PDF 98 kb)
Supplementary information, Figure S3
cFLIPs/l mRNA transcription and protein level. (PDF 89 kb)
Supplementary information, Figure S4
Representation of the hypothetic mechanism of AG-490-mediated increase of T tumour cell sensitivity to TRAIL. (PDF 114 kb)
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Lanuti, P., Bertagnolo, V., Pierdomenico, L. et al. Enhancement of TRAIL cytotoxicity by AG-490 in human ALL cells is characterized by downregulation of cIAP-1 and cIAP-2 through inhibition of Jak2/Stat3. Cell Res 19, 1079–1089 (2009). https://doi.org/10.1038/cr.2009.80
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DOI: https://doi.org/10.1038/cr.2009.80
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