A Novel Role of IGF1 in Apo2L-TRAIL-Mediated Apoptosis of Ewing Tumor CellsReport as inadecuate




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SarcomaVolume 2012 2012, Article ID 782970, 14 pages

Research Article

Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany

Institute of Food Chemistry, The University of Münster, Corrensstrasse 45, 48149 Münster, Germany

Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany

Department of Orthopedic Surgery, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany

Received 25 June 2012; Accepted 15 August 2012

Academic Editor: Maria Tsokos

Copyright © 2012 Frans van Valen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Insulin-like growth factor 1 IGF1 reputedly opposes chemotoxicity in Ewing sarcoma family of tumor ESFT cells. However, the effect of IGF1 on apoptosis induced by apoptosis ligand 2 Apo2L-tumor necrosis factor TNF- related apoptosis-inducing ligand TRAIL remains to be established. We find that opposite to the partial survival effect of short-term IGF1 treatment, long-term IGF1 treatment amplified Apo2L-TRAIL-induced apoptosis in Apo2L-TRAIL-sensitive but not resistant ESFT cell lines. Remarkably, the specific IGF1 receptor IGF1R antibody -IR3 was functionally equivalent to IGF1. Short-term IGF1 incubation of cells stimulated survival kinase AKT and increased X-linked inhibitor of apoptosis XIAP protein which was associated with Apo2L-TRAIL resistance. In contrast, long-term IGF1 incubation resulted in repression of XIAP protein through ceramide Cer formation derived from de novo synthesis which was associated with Apo2L-TRAIL sensitization. Addition of ceramide synthase CerS inhibitor fumonisin B1 during long-term IGF1 treatment reduced XIAP repression and Apo2L-TRAIL-induced apoptosis. Noteworthy, the resistance to conventional chemotherapeutic agents was maintained in cells following chronic IGF1 treatment. Overall, the results suggest that chronic IGF1 treatment renders ESFT cells susceptible to Apo2L-TRAIL-induced apoptosis and may have important implications for the biology as well as the clinical management of refractory ESFT.





Author: Frans van Valen, Henning Harrer, Marc Hotfilder, Uta Dirksen, Thomas Pap, George Gosheger, Hans-Ulrich Humpf, and Heribert

Source: https://www.hindawi.com/



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