Details
- Autor(en) / Beteiligte
- Titel
- Global phosphotyrosine proteomics identifies PKCδ as a marker of responsiveness to Src inhibition in colorectal cancer
- Ist Teil von
- PloS one, 2013-11, Vol.8 (11), p.e80207-e80207
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Sensitive and specific biomarkers of protein kinase inhibition can be leveraged to accelerate drug development studies in oncology by associating early molecular responses with target inhibition. In this study, we utilized unbiased shotgun phosphotyrosine (pY) proteomics to discover novel biomarkers of response to dasatinib, a small molecule Src-selective inhibitor, in preclinical models of colorectal cancer (CRC). We performed unbiased mass spectrometry shotgun pY proteomics to reveal the pY proteome of cultured HCT-116 colonic carcinoma cells, and then extended this analysis to HCT-116 xenograft tumors to identify pY biomarkers of dasatinib-responsiveness in vivo. Major dasatinib-responsive pY sites in xenograft tumors included sites on delta-type protein kinase C (PKCδ), CUB-domain-containing protein 1 (CDCP1), Type-II SH2-domain-containing inositol 5-phosphatase (SHIP2), and receptor protein-tyrosine phosphatase alpha (RPTPα). The pY313 site PKCδ was further supported as a relevant biomarker of dasatinib-mediated Src inhibition in HCT-116 xenografts by immunohistochemistry and immunoblotting with a phosphospecific antibody. Reduction of PKCδ pY313 was further correlated with dasatinib-mediated inhibition of Src and diminished growth as spheroids of a panel of human CRC cell lines. These studies reveal PKCδ pY313 as a promising readout of Src inhibition in CRC and potentially other solid tumors and may reflect responsiveness to dasatinib in a subset of colorectal cancers.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0080207Titel-ID: cdi_plos_journals_1449481289
- Format
- –
- Schlagworte
- Animals, Antigens, CD - metabolism, Antigens, Neoplasm, Binding sites, Bioindicators, Biomarkers, Biomarkers, Tumor - metabolism, Biomedical engineering, Caco-2 Cells, Cancer, Cell adhesion & migration, Cell Adhesion Molecules - metabolism, Cell Line, Tumor, Colorectal cancer, Colorectal carcinoma, Colorectal Neoplasms - metabolism, Dasatinib, Developmental biology, Drug development, Epidermal growth factor, HCT116 Cells, Humans, Immunoblotting, Immunohistochemistry, Inhibition, Inositol, Inositol polyphosphate 5-phosphatase, Inositol-1,4,5-trisphosphate 5-phosphatase, Kinases, Leukemia, Mass spectrometry, Mass spectroscopy, Medicine, Mice, Mice, Nude, Neoplasm Proteins - metabolism, Phosphatase, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases - metabolism, Phosphorylation, Phosphotyrosine, Phosphotyrosine - metabolism, Protein kinase C, Protein Kinase C-delta - metabolism, Protein Kinase Inhibitors - pharmacology, Protein-tyrosine-phosphatase, Proteins, Proteome - metabolism, Proteomics, Proteomics - methods, Pyrimidines - pharmacology, Receptor-Like Protein Tyrosine Phosphatases, Class 5 - metabolism, Science, Scientific imaging, Solid tumors, Spheroids, Src protein, src-Family Kinases - antagonists & inhibitors, src-Family Kinases - metabolism, Thiazoles - pharmacology, Tumors, Tyrosine, Xenografts, Xenotransplantation