Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts
Journal
Oncogene
Journal Volume
29
Journal Issue
22
Pages
3196-3207
Date Issued
2010
Author(s)
Abstract
Dasatinib, a dual Src family kinase and Abl inhibitor, is being tested clinically for the treatment of prostate cancer bone metastasis. Bidirectional interactions between osteoblasts and prostate cancer cells are critical in the progression of prostate cancer in bone, but the effect of dasatinib on osteoblasts is unknown. We found that dasatinib inhibited proliferation of primary mouse osteoblasts isolated from mouse calvaria and the immortalized MC3T3-E1 cell line. In calvarial osteoblasts from Col-luc transgenic mice carrying osteoblast-specific Col1α1 promoter reporter, luciferase activity was inhibited. Dasatinib also inhibited fibroblast growth factor-2-induced osteoblast proliferation, but strongly promoted osteoblast differentiation, as reflected by stimulation of alkaline phosphatase activity, osteocalcin secretion and osteoblast mineralization. To determine how dasatinib blocks proliferative signaling in osteoblasts, we analyzed the expression of a panel of tyrosine kinases, including Src, Lyn, Fyn, Yes and Abl, in osteoblasts. In the Src family kinases, only Src was activated at a high level. Abl was expressed at a low level in osteoblasts. Phosphorylation of Src-Y419 or Abl-Y245 was inhibited by dasatinib treatment. Knockdown of either Src or Abl by lenti-shRNA in osteoblasts enhances osteoblast differentiation, suggesting that dasatinib enhances osteoblast differentiation through inhibition of both Src and Abl. ? 2010 Macmillan Publishers Limited All rights reserved.
Subjects
Bone metastasis; Dasatinib; Osteoblast; Prostate cancer; Src family kinase
SDGs
Other Subjects
Abelson kinase; alkaline phosphatase; dasatinib; fibroblast growth factor 2; luciferase; protein kinase Fyn; protein kinase Lyn; protein kinase Yes; Abelson kinase; dasatinib; osteonectin; protein kinase inhibitor; protein tyrosine kinase; pyrimidine derivative; thiazole derivative; animal cell; article; calvaria; cell differentiation; cell proliferation; controlled study; drug mechanism; enzyme inhibition; enzyme phosphorylation; mouse; nonhuman; osteoblast; priority journal; transgenic mouse; animal; antagonists and inhibitors; biosynthesis; cell differentiation; cell growth; cytology; drug effects; enzymology; gene silencing; human; male; metabolism; osteoblast; phosphorylation; tumor invasion; Animals; Cell Differentiation; Cell Growth Processes; Gene Knockdown Techniques; Humans; Male; Mice; Mice, Transgenic; Neoplasm Invasiveness; Osteoblasts; Osteonectin; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Pyrimidines; src-Family Kinases; Thiazoles; Mus musculus; Animals; Cell Differentiation; Cell Growth Processes; Gene Knockdown Techniques; Humans; Male; Mice; Mice, Transgenic; Neoplasm Invasiveness; Osteoblasts; Osteonectin; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Pyrimidines; src-Family Kinases; Thiazoles
Type
journal article