Dual effects of IGFBP‐3 on endothelial cell apoptosis and survival: Involvement of the sphingolipid signaling pathways

Granata, Riccarda; Trovato, Letizia; Garbarino, Giovanni; Taliano, Marina; Ponti, Renata; Sala, G; Ghidoni, Riccardo; Ghigo, Ezio

doi:10.1096/fj.04-1618fje

Cited by 111 publications

(123 citation statements)

References 55 publications

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“…Data calculated using the KM Plotter online survival analysis tool (Györffy, et al 2010) DNA damage signaling As discussed earlier, IGFBP-3 can potentiate the induction of apoptosis by ceramide (Gill et al 1997) as well as other agents. In human umbilical vein endothelial cells (HUVECs), IGFBP-3 increased apoptosis induced by the DNA-damaging drug doxorubicin, but increased cell viability and inhibited apoptosis if the generation of ceramide in response to doxorubicin treatment was prevented by the drug fumonisin B1 (Granata et al 2004). Ceramide, which is generated either by de novo synthesis or by the action of sphingomyelinases on the membrane lipid sphingomyelin, is a precursor of sphingosine and thus also of S1P (Wymann and Schneiter 2008).…”

Section: Egfr Igf1r and Sphingosine Kinase Signalingmentioning

confidence: 99%

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

Baxter

2013

J. Cell Commun. Signal.

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In addition to its important role in the regulation of somatic growth by acting as the major circulating transport protein for the insulin-like growth factors (IGFs), IGF binding protein-3 (IGFBP-3) has a variety of intracellular ligands that point to its function within major signaling pathways. The discovery of its interaction with the retinoid X receptor has led to the elucidation of roles in regulating the function of several nuclear hormone receptors including retinoic acid receptor-α, Nur77 and vitamin D receptor. Its interaction with the nuclear hormone receptor peroxisome proliferator-activated receptor-γ is believed to be involved in regulating adipocyte differentiation, which is also modulated by IGFBP-3 through an interaction with TGFβ/Smad signaling. IGFBP-3 can induce apoptosis alone or in conjunction with other agents, and in different systems can activate caspases −8 and −9. At least two unrelated proteins (LRP1 and TMEM219) have been designated as receptors for IGFBP-3, the latter with a demonstrated role in inducing caspase-8-dependent apoptosis. In contrast, IGFBP-3 also has demonstrated roles in survival-related functions, including the repair of DNA double-strand breaks through interaction with the epidermal growth factor receptor and DNAdependent protein kinase, and the induction of autophagy through interaction with GRP78. The ability of IGFBP-3 to modulate the balance between pro-apoptotic and prosurvival sphingolipids by regulating sphingosine kinase 1 and sphingomyelinases may be integral to its role at the crossroads between cell death and survival in response to a variety of stimuli. The pleiotropic nature of IGFBP-3 activity supports the idea that IGFBP-3 itself, or pathways with which it interacts, should be investigated as targets of therapy for a variety of diseases.

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Section: Egfr Igf1r and Sphingosine Kinase Signalingmentioning

confidence: 99%

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

Baxter

2013

J. Cell Commun. Signal.

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“…[4][5][6][7][8] It may also have IGF-independent antitumor activities through cell-surface or intracellular protein interaction, its nuclear translocation, or its transcriptional regulation. 7,[9][10][11][12] However, the mechanisms that mediate IGFBP-3's IGF-independent antitumor activity have not been clearly defined.…”

Section: Introductionmentioning

confidence: 99%

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

Kim

Choi

Lee

et al. 2011

Blood

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Most antiangiogenic therapies currently being evaluated in clinical trials target the vascular endothelial growth factor pathway; however, the tumor vasculature can acquire resistance to vascular endothelial growth factor-targeted therapy by shifting to other angiogenesis mechanisms. Insulin-like growth factor binding protein-3 (IGFBP-3) has been reported to suppress tumor growth and angiogenesis by both IGF-dependent and IGFindependent mechanisms; however, understanding of its IGF-independent mechanisms is limited. We observed that IGFBP-3 blocked tumor angiogenesis and growth in non-small cell lung cancer and head and neck squamous cell carcinoma. Conditioned media from an IGFBP-3-treated non-small cell lung cancer cell line displayed a significantly decreased capacity to induce HUVEC proliferation and aortic sprouting. In cancer cells, IGFBP-3 directly interacted with Erk1/2, leading to inactivation of Erk1/2 and Elk-1, and suppressed transcription of early growth response protein 1 and its target genes, basic fibroblast growth factor and platelet-derived growth factor. These data suggest that IGF-independent Erk1/2 inactivation and decreased IGFBP-3-induced Egr-1 expression block the autocrine and paracrine loops of angiogenic factors in vascular endothelial and cancer cells. Together, these findings provide a molecular framework of IGFBP-3's IGF-independent antiangiogenic antitumor activities. IntroductionAngiogenesis, the formation of new capillaries from existing blood vessels, is essential to carcinogenic processes, including solid tumor formation, growth, invasion, and metastasis. 1 Most tumors can stimulate angiogenesis by switching on the production of numerous cytokines and growth factors, including fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs), and platelet-derived growth factors (PDGFs). 2 Several antiangiogenic agents are in various phases of clinical trials for human cancer; however, most of these agents target the VEGF signaling pathway. 3 Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated.Insulin-like growth factor-binding protein-3 (IGFBP-3), a member of a family of 6 IGFBPs, has demonstrated antiproliferative, proapoptotic, antiangiogenic, and antimetastatic activity in a variety of cancer cells. [4][5][6][7][8] It may also have IGF-independent antitumor activities through cell-surface or intracellular protein interaction, its nuclear translocation, or its transcriptional regulation. 7,[9][10][11][12] However, the mechanisms that mediate IGFBP-3's IGF-independent antitumor activity have not been clearly defined.The 82-kDa phosphoprotein transcription factor early growth response protein 1 (Egr-1), an immediate early gene product, has been implicated in multiple cellular processes, including cell growth, apoptosis, wound healing, and angiogenesis. Mitogenic stimuli, including serum, PDGF, peptide growth factors, and B-Raf, and nonmitogenic stresses, including ␥-irradiation and hypoxia, activate Egr-1 expre...

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“…Besides its endocrine effects, IGFBP3 has auto-and paracrine actions affecting cell mobility, adhesion, apoptosis, survival, and the cell cycle (14,15). Like the other IGFBPs, IGFBP3 has IGF1-independent effects.…”

mentioning

confidence: 99%

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Chang

Chan‐Ling

McFarland

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

128

106

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We asked whether the hypoxia-regulated factor, insulin-like growth factor binding protein-3 (IGFBP3), could modulate stem cell factor receptor (c-kit ؉ ), stem cell antigen-1 (sca-1 ؉ ), hematopoietic stem cell (HSC), or CD34 ؉ endothelial precursor cell (EPC) function. Exposure of CD34 ؉ EPCs to IGFBP3 resulted in rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. IGFBP3-expressing plasmid was injected into the vitreous of neonatal mice undergoing the oxygeninduced retinopathy (OIR) model. In separate studies, GFP-expressing HSCs were transfected with IGFBP3 plasmid and injected into the vitreous of OIR mice. Administering either IGFBP3 plasmid alone or HSCs transfected with the plasmid resulted in a similar reduction in areas of vasoobliteration, protection of the developing vasculature from hyperoxia-induced regression, and reduction in preretinal neovascularization compared to control plasmid or HSCs transfected with control plasmid. In conclusion, IGFBP3 mediates EPC migration, differentiation, and capillary formation in vitro. Targeted expression of IGFBP3 protects the vasculature from damage and promotes proper vascular repair after hyperoxic insult in the OIR model. IGFBP3 expression may represent a physiological adaptation to ischemia and potentially a therapeutic target for treatment of ischemic conditions. IGFBP3 ͉ angiogenesis ͉ retinopathy of prematurity V ascular damage associated with diabetic retinopathy and retinopathy of prematurity (ROP) results from tissue ischemia, and, subsequently, this ischemia leads to development of pathological neovascularization. Insulin-like growth factor 1 (IGF1) is required for normal retinal vascular development because vascular development is arrested in its absence despite the presence of VEGF (1). Development of ROP is associated with low levels of IGF1 (2) because the lack of IGF1 in the early neonatal period leads to the development of avascular retina, which results in ROP (3). However, unregulated IGF1 expression can lead to pathological neovascularization (4-13), and IGF1 receptor (IGF1R) antagonists are able to suppress retinal neovascularization in vivo by inhibiting VEGF signaling (1).The effects of IGF1 are mediated by IGF1R and modulated by complex interactions with IGF binding proteins (IGFBPs), which are also modulated at multiple levels. Six IGFBPs function as transporter proteins and storage pools for IGF1 in a tissue-and developmental stage-specific manner. Phosphorylation, proteolysis, polymerization (8), and cell or matrix association (9) regulates the functions of IGFBPs. Specific IGFBPs have been shown to either stimulate or inhibit IGF1 action (10).IGFBP3, the best studied and most abundant of these binding proteins, carries Ն75% of serum IGF1 and IGF2 in heterotrimeric complexes. Besides its endocrine effects, IGFBP3 has auto-and paracrine actions affecting cell mobility, adhesion, apoptosis, survival, and the cell cycle (14,15). Like the other IGFBPs, IGFBP3 has IGF1-in...

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Dual effects of IGFBP‐3 on endothelial cell apoptosis and survival: Involvement of the sphingolipid signaling pathways

Cited by 111 publications

References 55 publications

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

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

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

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

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