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Phosphoproteomic screen identifies potential therapeutic targets in melanoma.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2011 Jun; Vol. 9 (6), pp. 801-12. Date of Electronic Publication: 2011 Apr 26. - Publication Year :
- 2011
-
Abstract
- Therapies directed against receptor tyrosine kinases are effective in many cancer subtypes, including lung and breast cancer. We used a phosphoproteomic platform to identify active receptor tyrosine kinases that might represent therapeutic targets in a panel of 25 melanoma cell strains. We detected activated receptors including TYRO3, AXL, MERTK, EPHB2, MET, IGF1R, EGFR, KIT, HER3, and HER4. Statistical analysis of receptor tyrosine kinase activation as well as ligand and receptor expression indicates that some receptors, such as FGFR3, may be activated via autocrine circuits. Short hairpin RNA knockdown targeting three of the active kinases identified in the screen, AXL, HER3, and IGF1R, inhibited the proliferation of melanoma cells and knockdown of active AXL also reduced melanoma cell migration. The changes in cellular phenotype observed on AXL knockdown seem to be modulated via the STAT3 signaling pathway, whereas the IGF1R-dependent alterations seem to be regulated by the AKT signaling pathway. Ultimately, this study identifies several novel targets for therapeutic intervention in melanoma.
- Subjects :
- Apoptosis
Cell Line, Tumor
Cell Movement
Cell Proliferation
ErbB Receptors antagonists & inhibitors
ErbB Receptors genetics
ErbB Receptors metabolism
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
HEK293 Cells
Humans
Infant, Newborn
Melanocytes enzymology
Phosphorylation genetics
Proteomics
RNA, Small Interfering genetics
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Receptor Protein-Tyrosine Kinases genetics
Receptor, IGF Type 2 genetics
Receptor, IGF Type 2 metabolism
STAT3 Transcription Factor genetics
STAT3 Transcription Factor metabolism
Signal Transduction
Melanoma drug therapy
Melanoma enzymology
Phosphoproteins metabolism
Receptor Protein-Tyrosine Kinases metabolism
Skin Neoplasms drug therapy
Skin Neoplasms enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 9
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 21521745
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-10-0512