Nuclear effects: unexpected intracellular actions of insulin-like growth factor binding protein-3

Kw, Lee; Cohen, Pinchas

doi:10.1677/joe.0.1750033

Cited by 75 publications

(53 citation statements)

References 38 publications

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“…The in vivo data presented here complements a compendium of in vitro data in prostate cancer models, showing that IGFBP-3 induces apoptosis, in a manner that could be unrelated to its IGF binding (24,25); and that it mediates many tumorsuppressive effects of cytokines and hormones (26). IGFBP-3 is secreted and reuptaken rapidly to the nucleus via distinct endocytic pathways (7) and nuclear localization is mediated by importin-h pathway via a bipartite basic consensus sequence near its COOH terminus (27,28).…”

Section: Discussionsupporting

confidence: 53%

Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo

Liu

Lee²,

Li³

et al. 2005

Clinical Cancer Research

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We have previously identified the retinoid X receptor-a (RXRa) as an insulin-like growth factor binding protein-3 (IGFBP-3) nuclear binding partner, which is required for IGFBP-3-induced apoptosis. In the current study, we investigated the biological interactions of the RXR ligand, VTP194204 and rhIGFBP-3, in vitro and in vivo. In vitro, IGFBP-3 and VTP194204 individually induced apoptosis, and suppressed cell growth in prostate cancer cell lines in an additive manner. In vivo, LAPC-4 xenograft^bearing severe combined immunodeficiency mice treated daily with saline, IGFBP-3, and/or VTP194204 for 3 weeks showed no effect of individual treatments with IGFBP-3 or VTP194204 on tumor growth. However, the combination of IGFBP-3 and VTP194204 treatments inhibited tumor growth by 50% and induced a significant reduction in serum prostate-specific antigen levels. In terminal nucleotidyl transferase^mediated nick end labeling immunohistochemistry of LAPC-4 xenografts, there was modest induction of apoptosis with either IGFBP-3 or VTP194204 individual treatment, but combination therapy resulted in massive cell death, indicating that IGFBP-3 and VTP194204 have a synergistic effect in preventing tumor growth by apoptosis induction. In summary, this is an initial description of the successful therapeutic use of IGFBP-3 as a cancer therapy in vivo, and shows that combination treatment of IGFBP-3 and RXR ligand has a synergistic effect on apoptosis induction leading to substantial inhibition of prostate cancer xenograft growth. Taken together, these observations suggest that combination therapy with IGFBP-3 and RXR ligands may have therapeutic potential for prostate cancer treatment.The insulin-like growth factor (IGF) system is well recognized to play a critical role in cancer development. In particular, IGF binding proteins (IGFBP) have been proposed to act as growth inhibitory molecules through their IGF inhibitory effects. However, a direct IGF-independent role of IGFBPs, particularly IGFBP-3 in the regulation of apoptosis, has emerged over the last decade (1). A key intracellular role for IGFBP-3 was shown in 2000 with the discovery of the nuclear retinoid X receptor a (RXRa) as a binding partner for IGFBP-3. In that study, IGFBP-3 cotransfections potently and dose-dependently inhibited retinoic acid signaling via retinoic acid response element, but enhanced RXR-specific ligand signaling via the retinoid X response element, supporting a co-activator/repressor role for IGFBP-3 in transcription. In addition, IGFBP-3 had no discernible effects in an RXR knock-out line, indicating that RXR is required for IGFBP-3-induced apoptosis. In both androgen-dependent and -independent prostate cancer cell lines, additive effects of IGFBP-3 and RXR ligand on apoptosis were shown (2).Retinoids (including RXR ligands) are prime candidates for cancer chemoprevention because cancer is characterized by abnormal growth with lack of differentiation, which could be modified by retinoids. The nuclear retinoic acid receptors and RXRs media...

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Section: Discussionsupporting

confidence: 53%

Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo

Liu

Lee²,

Li³

et al. 2005

Clinical Cancer Research

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“…We found that mainly nuclear IGFBP-3 was targeted by ubiquitin/proteasome-dependent destruction; however, polyubiquitination was very low for IGFBP-3 expressed in the lumen of the membranous organelles. These findings suggest that ubiquitin/proteasome-dependent destruction of nuclear IGFBP-3 may play an important role for the control of cell proliferation and apoptosis by IGFBP-3 (36).…”

Section: Discussionmentioning

confidence: 81%

Nuclear Insulin-Like Growth Factor Binding Protein-3 Induces Apoptosis and Is Targeted to Ubiquitin/Proteasome–Dependent Proteolysis

et al. 2006

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Insulin-like growth factor binding protein-3 (IGFBP-3), the product of a tumor suppressor target gene, can modulate cell proliferation and apoptosis by IGF-I-dependent and IGF-Iindependent mechanisms. IGFBP-3 controls the bioavailability of IGFs in the extracellular environment and is known to be subject to degradation by various extracellular proteases. Although nuclear localization and functions of IGFBP-3 have been described in the past, we show as the novel features of this study that the abundance of nuclear IGFBP-3 is directly regulated by ubiquitin/proteasome-dependent proteolysis. We show that IGFBP-3 degradation depends on an active ubiquitin-E1 ligase, specific 26S proteasome inhibitors can efficiently stabilize nuclear IGFBP-3, and the metabolic halflife of nuclear IGFBP-3 is strongly reduced relative to cytoplasmic IGFBP-3. Nuclear IGFBP-3 is highly polyubiquitinated at multiple lysine residues in its conserved COOHterminal domain and stabilized through mutation of two COOH-terminal lysine residues. Moreover, we show that IGFBP-3, if ectopically expressed in the nucleus, can induce apoptotic cell death. These results suggest that ubiquitin/proteasomemediated proteolysis of IGFBP-3 may contribute to downregulation of apoptosis. (Cancer Res 2006; 66(6): 3024-33)

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“…In addition to IGF-1-and IGF-1R-dependent effects, recent reports have shown that IGFBP-3 may also act through distinct receptors and through nuclear translocation (14,15,20,21,29). Such IGF-1-and IGF-1R-independent mechanisms may play a role in the IGFBP-3 induction of apoptosis in Ewing cells, since in the absence of serum, wild-type IGFBP-3 is still able to trigger apoptosis, whereas a noninternalizable version of IGFBP-3 with a mutated NLS is inefficient.…”

Section: Discussionmentioning

confidence: 99%

EWS/FLI-1 Silencing and Gene Profiling of Ewing Cells Reveal Downstream Oncogenic Pathways and a Crucial Role for Repression of Insulin-Like Growth Factor Binding Protein 3

Prieur

Tirode

Cohen

et al. 2004

Molecular and Cellular Biology

376

327

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Ewing tumors are characterized by abnormal transcription factors resulting from the oncogenic fusion of EWS with members of the ETS family, most commonly FLI-1. RNA interference targeted to the junction between EWS and FLI-1 sequences was used to inactivate the EWS/FLI-1 fusion gene in Ewing cells and to explore the resulting phenotype and alteration of the gene expression profile. Loss of expression of EWS/FLI-1 resulted in the complete arrest of growth and was associated with a dramatic increase in the number of apoptotic cells. Gene profiling of Ewing cells in which the EWS/FLI-1 fusion gene had been inactivated identified downstream targets which could be grouped in two major functional clusters related to extracellular matrix structure or remodeling and regulation of signal transduction pathways. Among these targets, the insulin-like growth factor binding protein 3 gene (IGFBP-3), a major regulator of insulin-like growth factor 1 (IGF-1) proliferation and survival signaling, was strongly induced upon treating Ewing cells with EWS/FLI-1-specific small interfering RNAs. We show that EWS/FLI-1 can bind the IGFBP-3 promoter in vitro and in vivo and can repress its activity. Moreover, IGFBP-3 silencing can partially rescue the apoptotic phenotype caused by EWS/FLI-1 inactivation. Finally, IGFBP-3-induced Ewing cell apoptosis relies on both IGF-1-dependent and -independent pathways. These findings therefore identify the repression of IGFBP-3 as a key event in the development of Ewing's sarcoma.Ewing tumors, the second most frequent bone tumors in adolescents and young adults, are characterized by the presence of specific gene fusions which most frequently involve the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11 (8). Less frequently, EWS is fused with other members of the ETS family, including ERG, ETV1, E1A-F, or FEV (1). As a result of these gene fusions, tumor cells express a chimeric protein that contains the amino-terminal part of EWS and the DNA binding domain of the ETS transcription factor. EWS belongs to the TET family of proteins, which also includes TAF II 68 and TLS/FUS (4). All three proteins from this family have been shown to be involved in cancer-specific translocations, following a general scheme, which fuses the N-terminal domain of the TET partner to a variety of DNA binding domains, each fusion being highly specific for a tumor type. Numerous reports have addressed the mechanisms of tumoral transformation induced by TET fusion proteins and particularly EWS/FLI-1, the most frequent representative.Considerable attention has focused on the search for specific downstream target genes that may mediate EWS/FLI-1 transforming properties. Although the specificity of the EWS/FLI-1 fusion gene for Ewing tumors suggests that the cell context is critical for EWS/FLI-1-induced oncogenesis, the parental Ewing cell of origin is currently unknown. This issue precludes the development of homologous cell systems that may be particularly helpful to design strategies aimed at the identification of...

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Nuclear effects: unexpected intracellular actions of insulin-like growth factor binding protein-3

Cited by 75 publications

References 38 publications

Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo

Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo

Nuclear Insulin-Like Growth Factor Binding Protein-3 Induces Apoptosis and Is Targeted to Ubiquitin/Proteasome–Dependent Proteolysis

EWS/FLI-1 Silencing and Gene Profiling of Ewing Cells Reveal Downstream Oncogenic Pathways and a Crucial Role for Repression of Insulin-Like Growth Factor Binding Protein 3

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