A Novel Role of IGF1 in Apo2L/TRAIL-Mediated Apoptosis of Ewing Tumor Cells

Frans Van Valen,Uta Dirksen,Hans-Ulrich Humpf,George Gosheger,Thomas Pap,Heribert Jürgens,Henning Harrer,Marc Hotfilder

doi:10.1155/2012/782970

Frans Van Valen, Uta Dirksen + Show 6 more

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https://doi.org/10.1155/2012/782970

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Journal: Sarcoma	Publication Date: Jan 1, 2012
Citations: 56	License type: CC BY 3.0

Affiliation: University Hospital Münster, University of Münster

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 α-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.

Highlights

The Ewing sarcoma family of tumor (ESFT) of bone and soft tissue includes Ewing sarcoma, peripheral primitive neuroectodermal tumor, and Askin tumor which are among the most aggressive of pediatric malignancies
While 24 hours of Insulin-like growth factor 1 (IGF1) treatment caused suppression of Apo2L/TRAIL lethality (Figure 1(b)), 72 hours of IGF1 treatment caused amplification of Apo2L/TRAIL lethality (Figure 1(c)) in ESFT cell lines A17/95, A9423, ES-2, LAP-35, MHH-ES-1, and WE-68, which like VH-64 are all sensitive to Apo2L/TRAIL [13]
fumonisin B1 (FB1) did not modulate the inhibition of AKT activity induced by IGF1 after 72 hours (Figure 7(c)). These results suggest that Cer formation via de novo synthesis mediates X-linked inhibitor of apoptosis (XIAP) suppression and Apo2L/ TRAIL amplification in VH-64 cells in response to chronic IGF1 stimulation

Summary

Introduction

The Ewing sarcoma family of tumor (ESFT) of bone and soft tissue includes Ewing sarcoma, peripheral primitive neuroectodermal tumor, and Askin tumor which are among the most aggressive of pediatric malignancies. Improved insight into mechanisms of malignancy remains a high priority in ESFT research and is a prerequisite for the identification of new targeted therapies. Several lines of evidence suggest that IGF1 plays critical roles in the proliferation, metastasis, and survival of ESFT [2]. An IGF1-IGF1R autocrine circuit was suggested in some ESFT cells and addition of IGF1R antibody caused inhibition of cell proliferation [4]. IGF-binding protein 3 (IGFBP3) production is repressed in ESFT cells by oncogenic fusion proteins, which may allow for IGF1R activation through increased ligand binding [5]. IGF1 renders ESFT cells resistant to chemotherapeutic agents [6, 7]. Hofbauer et al [6] noticed that serum IGF1 is responsible for the induction

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