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

Naspi, Antimo; Panasiti, Vincenzo; Abbate, Franco; Roberti, Vincenzo; Devirgiliis, Valeria; Curzio, Michela; Borghi, Martina; Lozupone, Francesco; Carotti, Simone; Morini, Sergio; Gaudio, Eugenio; Calvieri, Stefano; Londei, Paola

doi:10.1371/journal.pone.0098641

Cited by 18 publications

(24 citation statements)

References 25 publications

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“…It is known that a main biological role of IGFBP‐3 is to regulate the PI3K pathway by controlling the binding of IGF1 to its receptor . In a previous paper, we showed that the anti‐migratory and anti‐invasive effects of IGFBP‐3 on melanoma cells are not mediated by the IGF1 receptor . To further exclude the possibility that the effect of IGFBP‐3 on the cellular levels of β‐catenin and Axin could be mediated by the PI3K pathway, we performed the following experiments.…”

Section: Resultsmentioning

confidence: 99%

IGFBP‐3 inhibits Wnt signaling in metastatic melanoma cells

Naspi

Zingariello

Sancillo

et al. 2016

Molecular Carcinogenesis

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In previous works, we have shown that insulin‐like growth factor‐binding protein‐3 (IGFBP‐3), a tissue and circulating protein able to bind to IGFs, decreases drastically in the blood serum of patients with diffuse metastatic melanoma. In agreement with the clinical data, recombinant IGFBP‐3 was found to inhibit the motility and invasiveness of cultured metastatic melanoma cells and to prevent growth of grafted melanomas in mice. The present work was aimed at identifying the signal transduction pathways underlying the anti‐tumoral effects of IGFBP‐3. We show that the anti‐tumoral effect of IGFBP‐3 is due to inhibition of the Wnt pathway and depends upon the presence of CD44, a receptor protein known to modulate Wnt signaling. Once it has entered the cell, IGFBP‐3 binds the Wnt signalosome interacting specifically with its component GSK‐3β. As a consequence, the β‐catenin destruction complex dissociates from the LRP6 Wnt receptor and GSK‐3β is activated through dephosphorylation, becoming free to target cytoplasmic β‐catenin which is degraded by the proteasomal pathway. Altogether, the results suggest that IGFBP‐3 is a novel and effective inhibitor of Wnt signaling. As IGFBP‐3 is a physiological protein which has no detectable toxic effects either on cultured cells or live mice, it might qualify as an interesting new therapeutic agent in melanoma, and potentially many other cancers with a hyperactive Wnt signaling. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

IGFBP‐3 inhibits Wnt signaling in metastatic melanoma cells

Naspi

Zingariello

Sancillo

et al. 2016

Molecular Carcinogenesis

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“…In glioblastoma, miR-21-mediated downregulation of IGFBP3 expression promotes tumorigenesis [ 72 ]. Recent evidence underscores that IGFBP3 exerts a specific inhibitory effect on melanoma growth and dissemination [ 74 ].…”

Section: Mir-21 and Malignant Melanomamentioning

confidence: 99%

MiR-21: an environmental driver of malignant melanoma?

Melnik

2015

J Transl Med

104

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Since the mid-1950’s, melanoma incidence has been rising steadily in industrialized Caucasian populations, thereby pointing to the pivotal involvement of environmental factors in melanomagenesis. Recent evidence underlines the crucial role of microRNA (miR) signaling in cancer initiation and progression. Increased miR-21 expression has been observed during the transition from a benign melanocytic lesion to malignant melanoma, exhibiting highest expression of miR-21. Notably, common BRAF and NRAS mutations in cutaneous melanoma are associated with increased miR-21 expression. MiR-21 is an oncomiR that affects critical target genes of malignant melanoma, resulting in sustained proliferation (PTEN, PI3K, Sprouty, PDCD4, FOXO1, TIPE2, p53, cyclin D1), evasion from apoptosis (FOXO1, FBXO11, APAF1, TIMP3, TIPE2), genetic instability (MSH2, FBXO11, hTERT), increased oxidative stress (FOXO1), angiogenesis (PTEN, HIF1α, TIMP3), invasion and metastasis (APAF1, PTEN, PDCD4, TIMP3). The purpose of this review is to provide translational evidence for major environmental and individual factors that increase the risk of melanoma, such as UV irradiation, chemical noxes, air pollution, smoking, chronic inflammation, Western nutrition, obesity, sedentary lifestyle and higher age, which are associated with increased miR-21 signaling. Exosomal miR-21 induced by extrinsic and intrinsic stimuli may be superimposed on mutation-induced miR-21 pathways of melanoma cells. Thus, oncogenic miR-21 signaling may be the converging point of intrinsic and extrinsic stimuli driving melanomagenesis. Future strategies of melanoma treatment and prevention should thus aim at reducing the burden of miR-21 signal transduction.

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“…Moreover, increased IGF-1 was observed without significant alteration in IGFBP-3 AUC in MAT following CSRT. IGFBP-3 is known to enhance IGF-1 retention in the circulation and block its access to the cognate receptor (IGF-1R)[ 15 , 16 ]. The effect of intense training on IGFBP3 in elderly is still conflicting[ 90 ], and further investigation in large population is needed to better understand its variability over time in response to intense training.…”

Section: Discussionmentioning

confidence: 99%

“…Serum IGFBP-3 is regulated by GH signaling [ 12 , 13 ] and reduced with advanced age [ 14 ]. The main function of IGFBP-3 is to permit IGF-1 transport and to regulate anti-proliferative and apoptotic effects through cell surface receptor by opposing IGF-1 action [ 15 , 16 ]. Moreover, IGFBP-3 is a valuable tool for diagnosis of GH perturbation during the aging process [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Combined sprint and resistance training abrogates age differences in somatotropic hormones

Sellami¹,

Dhahbi²,

Hayes³

et al. 2017

PLoS ONE

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The aim of this investigation was to compare serum growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) in response to a combined sprint and resistance training (CSRT) program in young and middle-aged men.Thirty-eight healthy, moderately trained men participated in this study. Young and middle-aged men were randomly assigned to, a young training group (YT = 10, 21.4±1.2yrs) ora young control group (YC = 9, 21.6±1.8 yrs), a middle-aged training group (MAT = 10, 40.4±2.1 yrs) or a middle-aged control group (MAC = 9, 40.5±1.8 yrs). Participants performed the Wingate Anaerobic Test (WAnT) before and after a 13-week CSRT program (three sessions per week). Blood samples were collected at rest, after warm-up, immediately post-WAnT, and 10 min post-WAnT. CSRT induced increases in GH at rest and in response to the WAnT in YT and MAT (P<0.05). CSRT-induced increases were observed for IGF-1 and IGFBP-3 at rest in MAT only (P<0.05). Pre-training, GH, IGF-1 and IGFBP-3 were significantly higher at rest and in response to the WAnT in young participants as compared to their middle-aged counterparts (P<0.05). Post-training, YT and MAT had comparable basal GH (P>0.05). In response to the WAnT, amelioration of the age-effect was observed between YT and MAT for IGF-1 and IGF-1/IGFBP-3 ratio following CSRT (P>0.05). These data suggest that CSRT increases the activity of the GH/IGF-1 axis at rest and in response to the WAnT in young and middle-aged men. In addition, CSRT reduces the normal age-related decline of somatotropic hormones in middle-age men.

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

Cited by 18 publications

References 25 publications

IGFBP‐3 inhibits Wnt signaling in metastatic melanoma cells

IGFBP‐3 inhibits Wnt signaling in metastatic melanoma cells

MiR-21: an environmental driver of malignant melanoma?

Combined sprint and resistance training abrogates age differences in somatotropic hormones

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