Volume 19, No 9, Sep 2009
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 19 Issue 9, September 2009: 1079-1089
ORIGINAL ARTICLES
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
Paola Lanuti1,2,*, Valeria Bertagnolo3,*, Laura Pierdomenico1,2, Adriana Bascelli1,2, Eugenio Santavenere1, Lapo Alinari4,5, Silvano Capitani3, Sebastiano Miscia1,2 and Marco Marchisio1,2
1Cell Signalling Unit, Department of Biomorphology, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 13, 66013 Chieti, Italy
2Center for Ageing Sciences (Ce.S.I.), "Università G.d'Annunzio" Foundation, Chieti, Italy
3Cell Signalling Unit, Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy
4Institute of Hematology and Medical Oncology "L.&A. Seragnoli", University of Bologna, Bologna, Italy
5Division of Haematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
Correspondence: Sebastiano Miscia,(s.miscia@unich.it)
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.
Cell Research (2009) 19:1079-1089. doi: 10.1038/cr.2009.80 published online 30 June 2009
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