Enhanced anti-melanoma efficacy of interferon alfa-2b via inhibition of Shp2.

Abstract

Interferon-α2b (IFN-α2b) is used to treat melanoma but there is a need to improve its efficacy. IFN-α2b signaling requires STAT1/STAT2 tyrosine phosphorylation and is subject to negative regulation by phosphatases. In this study, we determined whether inhibition of the protein tyrosine phosphatase Shp2 could enhance IFN-α2b responses in human melanoma cells. Shp2 knockdown increased IFN-α2b-stimulated STAT1 Tyr-701 phosphorylation and ISRE-luciferase activity even though it did not affect STAT2 Tyr-690 phosphorylation in A375 cells. In A375 tumor xenografts, Shp2 knockdown enhanced the anti-melanoma effect of IFN-α2b. Furthermore, the Shp2 inhibitor SPI-112Me increased the IFN-α2b-induced STAT1 activation and anti-proliferative response in A375 and SK-MEL-2 cells. These results demonstrate that inhibition of Shp2 can enhance the anti-melanoma activity of IFN-α2b.

• Authors: Hla Win-Piazza, Valentina E Schneeberger, Liwei Chen, Daniele Pernazza, Harshani R Lawrence, Said M Sebti, Nicholas J Lawrence, Jie Wu
• Journal: Cancer letters (Cancer Lett) Vol. 320 Issue 1 Pg. 81-5 (Jul 01 2012) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 22306001 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 3-(2-(5-(N-(4-fluorobenzyl)sulfamoyl)-2-oxoindolin-3-ylidene)hydrazinyl)benzoic acid methyl ester
• Indoles
• Interferon alpha-2
• Interferon-alpha
• RNA, Small Interfering
• Recombinant Proteins
• STAT1 Transcription Factor
• STAT1 protein, human
• Sulfonamides
• Extracellular Signal-Regulated MAP Kinases
• Protein Tyrosine Phosphatase, Non-Receptor Type 11

Topics

• Animals
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Combined Modality Therapy
• Drug Synergism
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Gene Knockdown Techniques
• Humans
• Indoles (pharmacology)
• Interferon alpha-2
• Interferon-alpha (pharmacology)
• Melanoma (drug therapy, enzymology, pathology)
• Mice
• Mice, Nude
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (antagonists & inhibitors, genetics)
• RNA, Small Interfering (administration & dosage, genetics)
• Recombinant Proteins (pharmacology)
• STAT1 Transcription Factor (metabolism)
• Sulfonamides (pharmacology)
• Xenograft Model Antitumor Assays