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Insulin-like-growth-factor-binding-protein-3 (IGFBP-3) contrasts melanoma progression in vitro and in vivo.

Naspi A, Panasiti V, Abbate F, Roberti V, Devirgiliis V, Curzio M, Borghi M, Lozupone F, Carotti S, Morini S, Gaudio E, Calvieri S, Londei P - PLoS ONE (2014)

Bottom Line: Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival.In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival.In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.

View Article: PubMed Central - PubMed

Affiliation: Istituto Pasteur-Fondazione Cenci-Bolognetti, Dpt. Biotecnologie Cellulari ed Ematologia, University of Rome Sapienza, Rome, Italy.

ABSTRACT
Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival. IGFBP-3 has been reported to decrease significantly in the blood serum of patients affected by certain cancers. In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival. In vitro treatment with IGFBP-3 of human and murine metastatic melanoma cell lines specifically inhibited the cells' migratory and invasive behaviour, inducing up-regulation of melanocytic differentiation markers such as tyrosinase activity and melanin content. A molecular analysis of the cellular pathways transducing the effect of IGFBP-3 implicated the Akt-GSK3β axis. Moreover, administration of IGFBP-3 in vivo to SCID mice inoculated with human metastatic melanoma cells strongly reduced or completely inhibited tumor growth. In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.

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IGFBP-3 acts independently of IGF-1.A) Western blot analysis for the detection of IGF-1 in lysates or culture media (CM) of Me501 cells. IGF-1 rec represents the positive control with recombinant IGF-1 (5 ng). B) Western blot analysis for detection of Tyr 1135-phosphorylation on the IGF-1 receptor β. Me501 cells were grown for 24 h in the presence of 10% serum (left panels) or in the absence of serum (right panels). For each group, treatments with IGFBP-3 or with anti-IGF-1 antibodies were performed. The amount of phosphorylated IGF-1-β receptor was quantified by densitometric analysis using total receptor (which remained unchanged) as the internal standard. C) Scratch-repair capacity of Me501 cells in the presence of anti-IGF1-antibodies and of IGFBP-3. The images shown are representative of experiments that were repeated at least three times.
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pone-0098641-g006: IGFBP-3 acts independently of IGF-1.A) Western blot analysis for the detection of IGF-1 in lysates or culture media (CM) of Me501 cells. IGF-1 rec represents the positive control with recombinant IGF-1 (5 ng). B) Western blot analysis for detection of Tyr 1135-phosphorylation on the IGF-1 receptor β. Me501 cells were grown for 24 h in the presence of 10% serum (left panels) or in the absence of serum (right panels). For each group, treatments with IGFBP-3 or with anti-IGF-1 antibodies were performed. The amount of phosphorylated IGF-1-β receptor was quantified by densitometric analysis using total receptor (which remained unchanged) as the internal standard. C) Scratch-repair capacity of Me501 cells in the presence of anti-IGF1-antibodies and of IGFBP-3. The images shown are representative of experiments that were repeated at least three times.

Mentions: Firstly, migration and invasion assays were performed in the absence of serum and hence in the absence of IGFs. The possibility that the cells themselves produced IGF-1 was discounted on the basis of western blot analysis of both cell lysates and culture media (Fig. 6A). IGF-1 mediated effects were further excluded by determining the state of activation of the IGF-1 receptor (IGF-1R).


Insulin-like-growth-factor-binding-protein-3 (IGFBP-3) contrasts melanoma progression in vitro and in vivo.

Naspi A, Panasiti V, Abbate F, Roberti V, Devirgiliis V, Curzio M, Borghi M, Lozupone F, Carotti S, Morini S, Gaudio E, Calvieri S, Londei P - PLoS ONE (2014)

IGFBP-3 acts independently of IGF-1.A) Western blot analysis for the detection of IGF-1 in lysates or culture media (CM) of Me501 cells. IGF-1 rec represents the positive control with recombinant IGF-1 (5 ng). B) Western blot analysis for detection of Tyr 1135-phosphorylation on the IGF-1 receptor β. Me501 cells were grown for 24 h in the presence of 10% serum (left panels) or in the absence of serum (right panels). For each group, treatments with IGFBP-3 or with anti-IGF-1 antibodies were performed. The amount of phosphorylated IGF-1-β receptor was quantified by densitometric analysis using total receptor (which remained unchanged) as the internal standard. C) Scratch-repair capacity of Me501 cells in the presence of anti-IGF1-antibodies and of IGFBP-3. The images shown are representative of experiments that were repeated at least three times.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048209&req=5

pone-0098641-g006: IGFBP-3 acts independently of IGF-1.A) Western blot analysis for the detection of IGF-1 in lysates or culture media (CM) of Me501 cells. IGF-1 rec represents the positive control with recombinant IGF-1 (5 ng). B) Western blot analysis for detection of Tyr 1135-phosphorylation on the IGF-1 receptor β. Me501 cells were grown for 24 h in the presence of 10% serum (left panels) or in the absence of serum (right panels). For each group, treatments with IGFBP-3 or with anti-IGF-1 antibodies were performed. The amount of phosphorylated IGF-1-β receptor was quantified by densitometric analysis using total receptor (which remained unchanged) as the internal standard. C) Scratch-repair capacity of Me501 cells in the presence of anti-IGF1-antibodies and of IGFBP-3. The images shown are representative of experiments that were repeated at least three times.
Mentions: Firstly, migration and invasion assays were performed in the absence of serum and hence in the absence of IGFs. The possibility that the cells themselves produced IGF-1 was discounted on the basis of western blot analysis of both cell lysates and culture media (Fig. 6A). IGF-1 mediated effects were further excluded by determining the state of activation of the IGF-1 receptor (IGF-1R).

Bottom Line: Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival.In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival.In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.

View Article: PubMed Central - PubMed

Affiliation: Istituto Pasteur-Fondazione Cenci-Bolognetti, Dpt. Biotecnologie Cellulari ed Ematologia, University of Rome Sapienza, Rome, Italy.

ABSTRACT
Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival. IGFBP-3 has been reported to decrease significantly in the blood serum of patients affected by certain cancers. In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival. In vitro treatment with IGFBP-3 of human and murine metastatic melanoma cell lines specifically inhibited the cells' migratory and invasive behaviour, inducing up-regulation of melanocytic differentiation markers such as tyrosinase activity and melanin content. A molecular analysis of the cellular pathways transducing the effect of IGFBP-3 implicated the Akt-GSK3β axis. Moreover, administration of IGFBP-3 in vivo to SCID mice inoculated with human metastatic melanoma cells strongly reduced or completely inhibited tumor growth. In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.

Show MeSH
Related in: MedlinePlus