Ovary and ovulation: Insulin-like growth factor binding protein-3 (IGFBP-3) serum concentrations and ovarian responsiveness in in-vitro fertilization

The proapoptotic, antiangiogenic, and antimetastatic activities of insulin-like growth factor binding protein-3 (IGFBP-3) through IGF-dependent or -independent mechanisms have been suggested in various types of human cancers. However, a mechanistic explanation of and downstream targets involved in the antimetastatic effect of IGFBP-3 is still lacking. In this study, by applying various in vitro and in vivo models, we show that IGFBP-3 suppresses migration and invasion of human head and neck squamous carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cells. Silencing IGFBP-3 expression elevated the migration and invasion of NSCLC and HNSCC cells in vitro and their local invasion and metastasis in vivo, whereas overexpression of IGFBP-3 decreased such prometastatic changes. Local invasion of 4-nitroquinoline-1-oxide (4-NQO)-induced HNSCC tumors was consistently significantly potentiated in Igfbp3 knockout mice compared with that in wild-type mice. Mechanistically, IGFBP-3 disrupted the protein stability of vimentin via direct binding and promoting its association with the E3 ligase FBXL14, causing proteasomal degradation. The C-terminal domain of IGFBP-3 and the head domain of vimentin are essential for their interaction. These results provide a molecular framework for IGFBP-3′s IGF-independent antimetastatic and antitumor activities.

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Insulin-Like-Growth-Factor-Binding-Protein-3 (IGFBP-3) Contrasts Melanoma Progression In Vitro and In Vivo

PLoS ONE ◽

10.1371/journal.pone.0098641 ◽

2014 ◽

Vol 9 (6) ◽

pp. e98641 ◽

Cited By ~ 10

Author(s):

Antimo Naspi ◽

Vincenzo Panasiti ◽

Franco Abbate ◽

Vincenzo Roberti ◽

Valeria Devirgiliis ◽

...

Keyword(s):

Growth Factor ◽

Binding Protein ◽

Insulin Like Growth Factor ◽

Factor Binding ◽

Melanoma Progression ◽

Igfbp 3

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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

Molecular and Cellular Biology ◽

10.1128/mcb.24.16.7275-7283.2004 ◽

2004 ◽

Vol 24 (16) ◽

pp. 7275-7283 ◽

Cited By ~ 281

Author(s):

Alexandre Prieur ◽

Franck Tirode ◽

Pinchas Cohen ◽

Olivier Delattre

Keyword(s):

Growth Factor ◽

Fusion Gene ◽

Binding Protein ◽

Gene Profiling ◽

Insulin Like Growth Factor ◽

Small Interfering Rnas ◽

Factor Binding ◽

Igfbp 3

ABSTRACT 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.

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Inhibition of adipocyte differentiation by insulin-like growth factor-binding protein-3

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90846.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. E654-E663 ◽

Cited By ~ 68

Author(s):

Sophie S. Y. Chan ◽

Lynette J. Schedlich ◽

Stephen M. Twigg ◽

Robert C. Baxter

Keyword(s):

Growth Factor ◽

Adipocyte Differentiation ◽

Binding Protein ◽

Peroxisome Proliferator ◽

Insulin Like Growth Factor ◽

Plasminogen Activator Inhibitor 1 ◽

Gene Markers ◽

Factor Binding ◽

Igfbp 3

Insulin-like growth factor-binding protein-3 (IGFBP-3) interacts with the type II nuclear receptors retinoid X receptor (RXR)α and retinoic acid receptor-α and modulates their transcriptional activity. Peroxisome proliferator-activated receptor (PPAR)γ, a related nuclear receptor that dimerizes with RXRα, plays an important role in adipocyte differentiation. IGFBP-3 is regulated during adipocyte differentiation, but its role in this process is unknown. We demonstrate that IGFBP-3 interferes with the PPARγ-dependent processes of adipocyte differentiation and maintenance of the gene expression characteristic of mature adipocytes. Treatment of adipocytes with exogenous IGFBP-3, but not an IGFBP-3 mutant that does not bind RXRα or PPARγ, decreased markers of adipocyte differentiation, PPARγ, and resistin but increased the preadipocyte marker plasminogen activator inhibitor-1. Furthermore, expression of human IGFBP-3, but not the IGFBP-3 mutant, by preadipocytes inhibited preadipocyte differentiation as determined by gene markers and lipid accumulation. IGFBP-3 interacted with PPARγ in vitro and in 3T3-L1 adipocyte lysates and inhibited PPARγ heterodimerization with RXRα in vitro. Wild-type IGFBP-3, but not mutant IGFBP-3, blocked ligand-induced transactivation of PPAR response element in 3T3-L1 cells. The observation that IGFBP-3 inhibits adipocyte differentiation and impacts on the PPARγ system suggests a role for IGFBP-3 in the pathogenesis of obesity and insulin resistance.

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