Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer.

Abstract

Insulin-like growth factor-binding protein-3 (IGFBP-3), a major regulator of endocrine actions of IGFs, is a p53-regulated potent apoptotic factor and is significantly suppressed in a variety of cancers. Recent epidemiologic studies suggest that IGFBP-3 contributes to cancer risk protection in a variety of cancers, and a polymorphic variation of IGFBP-3 influences cancer risk, although other studies vary in their conclusions. Some antiproliferative actions of IGFBP-3 have been reported to be independent of IGFs, but the precise biochemical/molecular mechanisms of IGF-independent, antiproliferative actions of IGFBP-3 are largely unknown. Here we report a new cell death receptor, IGFBP-3R, that is a single-span membrane protein and binds specifically to IGFBP-3 but not other IGFBP species. Expression analysis of IGFBP-3 and IGFBP-3R indicates that the IGFBP-3/IGFBP-3R axis is impaired in breast and prostate cancer. We also provide evidence for anti-tumor effect of IGFBP-3R in vivo using prostate and breast cancer xenografts in athymic nude mice. Further in vitro studies demonstrate that IGFBP-3R mediates IGFBP-3-induced caspase-8-dependent apoptosis in various cancer cells. Knockdown of IGFBP-3R attenuated IGFBP-3-induced caspase activities and apoptosis, whereas overexpression of IGFBP-3R enhanced IGFBP-3 biological effects. IGFBP-3R physically interacts and activates caspase-8, and knockdown of caspase-8 expression or activity inhibited IGFBP-3/IGFBP-3R-induced apoptosis. Here, we propose that IGFBP-3R represents a novel cell death receptor and is essential for the IGFBP-3-induced apoptosis and tumor suppression. Thus, the IGFBP-3/IGFBP-3R axis may provide therapeutic and prognostic value for the treatment of cancer.

• Authors: Angela R Ingermann, Yong-Feng Yang, Jinfeng Han, Aki Mikami, Amanda E Garza, Lathika Mohanraj, Lingbo Fan, Michael Idowu, Joy L Ware, Ho-Seong Kim, Dae-Yeol Lee, Youngman Oh
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 39 Pg. 30233-46 (Sep 24 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20353938 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• IGFBP-3R protein, human
• IGFBP3 protein, human
• Insulin-Like Growth Factor Binding Protein 3
• Insulin-Like Growth Factor Binding Proteins
• Membrane Proteins
• Neoplasm Proteins
• Receptors, Cell Surface
• CASP8 protein, human
• Caspase 8

Topics

• Animals
• Apoptosis
• Base Sequence
• Breast Neoplasms (genetics, metabolism, pathology)
• Caspase 8 (genetics, metabolism)
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Gene Knockdown Techniques
• Humans
• Insulin-Like Growth Factor Binding Protein 3
• Insulin-Like Growth Factor Binding Proteins (genetics, metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Nude
• Molecular Sequence Data
• Neoplasm Proteins (genetics, metabolism)
• Neoplasm Transplantation
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Receptors, Cell Surface (genetics, metabolism)
• Transplantation, Heterologous