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Inhibition of IGF-1R-dependent PI3K activation sensitizes colon cancer cells specifically to DR5-mediated apoptosis but not to rhTRAIL

Article type: Research Article

Authors: Pennarun, Bodvael; | Kleibeuker, Jan H. | Oenema, Tjitske | Stegehuis, Janet H. | de Vries, Elisabeth G.E. | de Jong, Steven;

Affiliations: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands | Department of Gastroenterology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Note: [] Corresponding author: Steven de Jong, PhD, Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Tel.: +31 50 3612964; Fax: +31 50 3614862; E-mail: [email protected].

Keywords: DR4, DR5, TRAIL, PI3K, colon cancer

DOI: 10.3233/ACP-CLO-2010-0549

Journal: Analytical Cellular Pathology, vol. 33, no. 5-6, pp. 229-244, 2010

Published: 2010
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Abstract

Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) initiates apoptosis in tumor cells upon binding to its cognate agonistic receptors, death receptors 4 and 5 (DR4 and DR5). The activity of the insulin-like growth factor 1 (IGF-1) survival pathway is often increased in cancer, influencing both cell proliferation and apoptosis. We hypothesized that inhibiting the IGF-1 receptor (IGF-1R) using NVP-AEW541, a small molecular weight tyrosine kinase inhibitor of the IGF-1R, could increase death receptor (DR)-mediated apoptosis in colon cancer cells.

Methods: The analyses were performed by caspase assay, flow cytometry, Western blotting, immunoprecipitation and fluorescent microscopy.

Results: Preincubation with NVP-AEW541 surprisingly decreased apoptosis induced by recombinant human TRAIL (rhTRAIL) or an agonistic DR4 antibody while sensitivity to an agonistic DR5 antibody was increased. NVP-AEW541 could inhibit IGF-1-induced activation of the phosphatidylinositol 3-kinase (PI3K) pathway. The effects of the PI3K inhibitor LY294002 on TRAIL-induced apoptosis were similar to those of NVP-AEW541, further supporting a role for IGF-1R-mediated activation of PI3K. We show that PI3K inhibition enhances DR5-mediated caspase 8 processing but also lowers DR4 membrane expression and DR4-mediated caspase 8 processing. Inhibition of PI3K reduced rhTRAIL sensitivity independently of the cell line preference for either DR4- or DR5-mediated apoptosis signaling.

Conclusions: Our study indicates that individual effects on DR4 and DR5 apoptosis signaling should be taken into consideration when combining DR-ligands with PI3K inhibition.

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