1. ¹Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, Bristol, UK
2. ²Montefiore Medical Center, Department of Oncology, Bronx, NY, USA
3. ³MRC Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, UK

Correspondence: AC Williams, Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK. Tel: +44 0117 9287892; Fax: +44 0117 9287896; E-mail: Ann.C.Williams@Bristol.ac.uk

Received 13 July 2005; Revised 13 February 2006; Accepted 22 February 2006; Published online 28 April 2006.

Abstract

There is growing evidence that the insulin-like growth factor-binding protein 3 (IGFBP-3) can have IGF-independent effects on cell growth. However, despite the fact that IGFBP-3 has been reported to be both antiproliferative and proapoptotic, the molecular mechanisms underlying the action of IGFBP-3 have not been elucidated. We report that although addition of IGFBP-3 (either synthetic or secreted protein) had no effect on cell survival, IGFBP-3 (100 ng/ml) significantly enhanced TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death in colonic carcinoma-derived cell lines (20–30% depending on cell line), whereas it had no effect on the survival of the TRAIL-resistant adenoma-derived cells. Both addition of IGFBP-3 protein to cell cultures or enforced expression of IGFBP-3 in the HT29 carcinoma cell line inhibited nuclear factor kappa B (NF-B) activation in response to the induction of apoptosis by TRAIL. We propose that IGFBP-3 is a non-toxic NF-B inhibitor, which could be used as an adjuvant in the treatment of colon cancer.