Insulin-like growth factor binding protein 3 (IGFBP-3) potentiates TRAIL-induced apoptosis of human colorectal carcinoma cells through inhibition of NF-kappaB.
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-kappaB) activation in response to the induction of apoptosis by TRAIL. We propose that IGFBP-3 is a non-toxic NF-kappaB inhibitor, which could be used as an adjuvant in the treatment of colon cancer.
Williams
A C
AC
Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, Bristol, UK. Ann.C.Williams@Bristol.ac.uk
Smartt
H
H
H-Zadeh
A M
AM
Macfarlane
M
M
Paraskeva
C
C
Collard
T J
TJ
D000236:Adenoma / Q000503:physiopathology*; D017209:Apoptosis; D002277:Carcinoma / Q000503:physiopathology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000503:physiopathology*; D019073:HT29 Cells; D006801:Humans; D020672:I-kappa B Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D020672:I-kappa B Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D000072000:NF-KappaB Inhibitor alpha