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 singlespan 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.Insulin-like growth factor-binding proteins (IGFBPs) 3 are integral components of the IGF system and modulate biological actions of IGFs such as cellular proliferation, differentiation, increase in metabolic activity, and cell survival (1). Apart from its ability to inhibit or enhance IGF actions, all the IGFBPs, IGFBP-1 to -6, have been reported to exert distinct biological actions such as cell proliferation, differentiation, migration, angiogenesis, and apoptosis through an IGF/IGF-I receptor (IGF-IR)-independent manner (2-7). These intrinsic biological activities of IGFBPs appear to be critical to cardiogenesis, vascular development, and pathogenesis of cancer.IGFBP-3, the most abundant IGFBP species in serum, circulates as a 150-kDa ternary complex with an acid-labile subunit and IGF peptide (1-3). Classically, the principal function of IGFBP-3 has been to transport IGFs, protecting them from rapid clearance and/or degradation, and modulating IGF bioavailability to cell-surface IGF receptors (8 -9). Many studies have reported that IGFBP-3 exhibits distinct biological effects independent of the IGF/IGF-IR axis, in particular cell growth inhibition and induction of apoptosis in a variety of cancer cells (10 -14). IGFBP-3 was shown to exert its IGF/IGF-IR-independent, antiproliferative actions via ...

Prohibitin-2 Binding Modulates Insulin-like Growth Factor-binding Protein-6 (IGFBP-6)-induced Rhabdomyosarcoma Cell Migration

“…PHB2 Is a Cell Surface Protein That Binds IGFBP-6-Although a number of IGF-independent actions of IGFBPs have been described via distinct mechanisms (34), there is limited information regarding cell surface proteins ("IGFBP receptors") that are responsible for these actions (35,36). IGFBP-1 and -2 interact with cell surface integrins to modulate cell migration and adhesion via Arg-Gly-Asp (RGD) sequences in their C-terminal domains (37,38).…”

“…IGFBP-1 and -2 interact with cell surface integrins to modulate cell migration and adhesion via Arg-Gly-Asp (RGD) sequences in their C-terminal domains (37,38). IGFBP-3 binds to a cell death receptor, IGFBP-3R, which mediates anti-tumor effects in breast and prostate cancer (36). IGFBP-4 binds to a Wnt receptor (Frizzled 8) and low density lipoprotein receptor-related protein 6, a Wnt co-receptor, to enhance cardiomyocyte differentiation (35).…”

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

“…In contrast to members of the tumor necrosis factor (TNF) receptor family and other proteins designated as death receptors, it does not contain the characteristic motif known as a death domain, which is involved in formation of the "death-inducing signaling complex" (DISC) and activation of caspase-8 (Park 2011). However it was described by the authors as a death receptor because in the presence of IGFBP-3, it induces caspase-8-dependent apoptosis (Ingermann, et al 2010). In prostate and breast cancer xenograft tumors in athymic mice, overexpression of IGFBP3-R caused some inhibition of tumor growth.…”

“…Subsequently a novel cell "death receptor" involved in IGFBP-3 action was identified (Ingermann, et al 2010) and designated as IGFBP-3R (a name previously given to LRP1/TβRV). This protein, encoded by the gene TMEM219 (transmembrane protein 219), contains 240 amino acids, i.e.…”

Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1–mediated transcriptional events

“…The intracellular translocalization of IGFBP-3 may have been mediated by membrane receptors, as proposed in previous studies. [55][56][57] In this study, recombinant IGFBP-3 translocated through the membranes into the cytoplasm. Additional mechanisms underlying the IGFBP-3-mediated inactivation of Erk1/2 should be explored (such as whether IGFBP-3's binding to surface receptors triggers phosphatases to dephosphorylate Erk1/2), our current data provide a schematic model in which IGFBP-3 directly binds to Erk1/2 and inhibits its activation, thereby preventing Elk-1 phosphorylation.…”