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

 Angela R. Ingermann  ;  Yong-Feng Yang  ;  Jinfeng Han  ;  Aki Mikami  ;  Ama E. Garza  ;  Lathika Mohanraj  ;  Lingbo Fan  ;  Michael Idowu  ;  Joy L. Ware  ;  Ho-Seong Kim  ;  Dae-Yeol Lee  ;  Youngman Oh 
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.285(39) : 30233-30246, 2010 
Journal Title
Issue Date
Animals ; Apoptosis* ; Base Sequence ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism* ; Breast Neoplasms/pathology ; Caspase 8/genetics ; Caspase 8/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 ; Insulin-Like Growth Factor Binding Proteins/metabolism* ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism* ; Mice ; Mice, Nude ; Molecular Sequence Data ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism* ; Neoplasm Transplantation ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism* ; Prostatic Neoplasms/pathology ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/metabolism* ; Transplantation, Heterologous
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
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1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ho Seong(김호성) ORCID logo https://orcid.org/0000-0003-1135-099X
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