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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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Analysis by phosphor-proteomic arrays of signal-transduction pathways involving in mediating IGFBP-3 action.(A) Phosphorylation state of the indicated markers in primary (WM 793, light grey) and metastatic (Me501, dark grey) human melanoma cells, untreated. (B) WM 793 cells before (light grey) and after (dark grey) treatment with IGFBP-3 (C) Me501 cells before (light grey) and after (dark grey) treatment with IGFBP-3. The assays were performed and quantified as described in the Methods. All determinations were repeated at least three times (D) Western blot analysis of the phosphorylation state of Akt (Ser 473) in Me501 cells untreated or treated with IGFBP-3 for the indicated times. pAKT 473 =  phosphor-(Ser473); AKT =  total AKT: Tub =  tubulin. The gel shown is representative of experiments that were repeated at least three times.
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pone-0098641-g007: Analysis by phosphor-proteomic arrays of signal-transduction pathways involving in mediating IGFBP-3 action.(A) Phosphorylation state of the indicated markers in primary (WM 793, light grey) and metastatic (Me501, dark grey) human melanoma cells, untreated. (B) WM 793 cells before (light grey) and after (dark grey) treatment with IGFBP-3 (C) Me501 cells before (light grey) and after (dark grey) treatment with IGFBP-3. The assays were performed and quantified as described in the Methods. All determinations were repeated at least three times (D) Western blot analysis of the phosphorylation state of Akt (Ser 473) in Me501 cells untreated or treated with IGFBP-3 for the indicated times. pAKT 473 =  phosphor-(Ser473); AKT =  total AKT: Tub =  tubulin. The gel shown is representative of experiments that were repeated at least three times.

Mentions: Fig. 7A shows the phosphor-proteome profiles of the primary and metastatic lines WM793 and Me501 in the absence of any treatment. As predicted by their genetic background, both lines had an active RAS-RAF-ERK pathway, confirming the central role thereof in melanoma development. However, the metastatic cells differed from the primary ones in having highly phosphorylated Akt (Ser 473) and p38 α/β kinases. Accordingly, certain downstream targets of Akt, such as GSK3β and mTOR, were also up-phosphorylated compared to the primary cell line.


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)

Analysis by phosphor-proteomic arrays of signal-transduction pathways involving in mediating IGFBP-3 action.(A) Phosphorylation state of the indicated markers in primary (WM 793, light grey) and metastatic (Me501, dark grey) human melanoma cells, untreated. (B) WM 793 cells before (light grey) and after (dark grey) treatment with IGFBP-3 (C) Me501 cells before (light grey) and after (dark grey) treatment with IGFBP-3. The assays were performed and quantified as described in the Methods. All determinations were repeated at least three times (D) Western blot analysis of the phosphorylation state of Akt (Ser 473) in Me501 cells untreated or treated with IGFBP-3 for the indicated times. pAKT 473 =  phosphor-(Ser473); AKT =  total AKT: Tub =  tubulin. The gel shown is 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-g007: Analysis by phosphor-proteomic arrays of signal-transduction pathways involving in mediating IGFBP-3 action.(A) Phosphorylation state of the indicated markers in primary (WM 793, light grey) and metastatic (Me501, dark grey) human melanoma cells, untreated. (B) WM 793 cells before (light grey) and after (dark grey) treatment with IGFBP-3 (C) Me501 cells before (light grey) and after (dark grey) treatment with IGFBP-3. The assays were performed and quantified as described in the Methods. All determinations were repeated at least three times (D) Western blot analysis of the phosphorylation state of Akt (Ser 473) in Me501 cells untreated or treated with IGFBP-3 for the indicated times. pAKT 473 =  phosphor-(Ser473); AKT =  total AKT: Tub =  tubulin. The gel shown is representative of experiments that were repeated at least three times.
Mentions: Fig. 7A shows the phosphor-proteome profiles of the primary and metastatic lines WM793 and Me501 in the absence of any treatment. As predicted by their genetic background, both lines had an active RAS-RAF-ERK pathway, confirming the central role thereof in melanoma development. However, the metastatic cells differed from the primary ones in having highly phosphorylated Akt (Ser 473) and p38 α/β kinases. Accordingly, certain downstream targets of Akt, such as GSK3β and mTOR, were also up-phosphorylated compared to the primary cell line.

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