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.
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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)
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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
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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
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