Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells.
Src family kinases (SFK) are currently being investigated as targets for treatment strategies in various cancers. The novel SFK/Abl inhibitor, dasatinib (BMS-354825), is a promising therapeutic agent with oral bioavailability. Dasatinib has been shown to inhibit growth of Bcr-Abl-dependent chronic myeloid leukemia xenografts in nude mice. Dasatinib also has been shown to have activity against cultured human prostate and breast cancer cells. However, the molecular mechanism by which dasatinib acts on epithelial tumor cells remains unknown. In this study, we show that dasatinib blocks the kinase activities of the SFKs, Lyn, and Src, in human prostate cancer cells at low nanomolar concentrations. Moreover, focal adhesion kinase and Crk-associated substrate (p130(CAS)) signaling downstream of SFKs are also inhibited at similar concentrations of dasatinib. Consistent with inhibition of these signaling pathways, dasatinib suppresses cell adhesion, migration, and invasion of prostate cancer cells at low nanomolar concentrations. Therefore, dasatinib has potential as a therapeutic agent for metastatic prostate cancers harboring activated SFK and focal adhesion kinase signaling.
Nam
Sangkil
S
Molecular Oncology and Biostatistics Programs, H. Lee Moffitt Cancer Center and Research Institute, Department of Pathology, University of South Florida College of Medicine, Tampa, Florida.
Kim
Donghwa
D
Cheng
Jin Q
JQ
Zhang
Shumin
S
Lee
Ji-Hyun
JH
Buettner
Ralf
R
Mirosevich
Janni
J
Lee
Francis Y
FY
Jove
Richard
R
D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D050719:Crk-Associated Substrate Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D000069439:Dasatinib