Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells.
Src family kinases (SFK) are involved in regulating a multitude of biological processes, including cell adhesion, migration, proliferation, and survival, depending on the cellular context. Therefore, although SFKs are currently being investigated as potential targets for treatment strategies in various cancers, the biological responses to inhibition of SFK signaling in any given tumor type are not predictable. Dasatinib (BMS-354825) is a dual Src/Abl kinase inhibitor with potent antiproliferative activity against hematologic malignancies harboring activated BCR-ABL. In this study, we show that dasatinib blocks migration and invasion of human melanoma cells without affecting proliferation and survival. Moreover, dasatinib completely inhibits SFK kinase activity at low nanomolar concentrations in all eight human melanoma cell lines investigated. In addition, two known downstream targets of SFKs, focal adhesion kinase and Crk-associated substrate (p130(CAS)), are inhibited with similar concentrations and kinetics. Consistent with inhibition of these signaling pathways and invasion, dasatinib down-regulates expression of matrix metalloproteinase-9. We also provide evidence that dasatinib directly inhibits kinase activity of the EphA2 receptor tyrosine kinase, which is overexpressed and/or overactive in many solid tumors, including melanoma. Thus, SFKs and downstream signaling are implicated as having key roles in migration and invasion of melanoma cells.
Buettner
Ralf
R
Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA. RBuettner@coh.org
Mesa
Tania
T
Vultur
Adina
A
Lee
Frank
F
Jove
Richard
R
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D000069439:Dasatinib; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D036104:Receptor, EphA2; D019061:src-Family Kinases; D020780:Matrix Metalloproteinase 9; D000069439:Dasatinib