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

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An Erratum to this article was published on 01 June 2011

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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Authors and Affiliations

  1. Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ, Groningen, the Netherlands

    Bodvael Pennarun, Tjitske Oenema, Janet H. Stegehuis, Elisabeth G. E. de Vries & Steven de Jong

  2. Department of Gastroenterology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ, Groningen, the Netherlands

    Bodvael Pennarun & Jan H. Kleibeuker

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  1. Bodvael Pennarun
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  2. Jan H. Kleibeuker
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  4. Janet H. Stegehuis
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  5. Elisabeth G. E. de Vries
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Correspondence to Steven de Jong.

Additional information

This paper is a reprint of ‘Inhibition of IGF-1R-dependent PI3K activation sensitizes colon cancer cells specifically to DR5-mediated apoptosis but not to rhTRAIL, Bodvael Pennarun, Jan H. Kleibeuker, Tjitske Oenema, Janet H. Stegehuis, Elisabeth G.E. de Vries, Steven de Jong’ originally published in Analytical Cellular Pathology/Cellular Oncology, Volume 33, number 5–6, 2010, pp. 229–244, IOS Press.

An erratum to this article can be found at http://dx.doi.org/10.1007/s13402-011-0055-3

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Pennarun, B., Kleibeuker, J.H., Oenema, T. et al. Inhibition of IGF-1R-dependent PI3K activation sensitizes colon cancer cells specifically to DR5-mediated apoptosis but not to rhTRAIL. Cell Oncol. 34, 245–259 (2011). https://doi.org/10.1007/s13402-011-0033-9

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