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Enhancement of Tumor Necrosis Factor--Induced Growth Inhibition by Insulin-Like Growth Factor-Binding Protein-5 (IGFBP-5), But Not IGFBP-3 in Human Breast Cancer Cells

Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia

Address all correspondence and requests for reprints to: Dr. Alison J. Butt, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia. E-mail: abutt{at}garvan.org.au.

Expression of IGF-binding protein-3 (IGFBP-3) and IGFBP-5 in human breast cancer cells induces apoptosis and is associated with modulations in Bcl-2 proteins, suggesting that these IGFBPs induce an intrinsic apoptotic pathway. In this study we demonstrate that although both IGFBPs induced the activation of caspase-8 and caspase-9, the expression of IGFBP-5, but not IGFBP-3, sensitized MDA-MB-231 breast cancer cells to the inhibitory effects of TNF. This sensitivity to TNF was associated with a block in nuclear factor-B-mediated cell survival signals. IGFBP-5 expression was also associated with a caspase-8-independent activation of Bid, increased levels of cytosolic second mitochondria-derived activator of caspase (Smac)/direct inhibitor of apoptosis proteins (IAP) binding protein with low pI (DIABLO), and an enhanced phosphorylation of c-Jun N-terminal kinase, both basally and in response to TNF. These results suggest that IGFBP-5 expression may influence extrinsic apoptotic pathways via a differential modulation of downstream cell survival and cell death pathways. Furthermore, although IGFBP-3 and IGFBP-5 share much structural and functional homology, they can modulate distinct apoptotic pathways in human breast cancer cells.

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