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The tyrosine kinase inhibitor TAS-115 that blocks VEGF receptor and hepatocyte growth factor receptor MET signaling exhibits antitumor properties in xenografts of human gastric carcinoma. In this study, we have evaluated the efficacy of TAS-115 in preventing prostate cancer metastasis to the bone and bone destruction using the PC3 cell line. When PC3 cells were injected into proximal tibiae in nude mouse, severe trabecular and cortical bone destruction and subsequent tumor growths were detected. Oral administration of TAS-115 almost completely inhibited both PC3-induced bone loss and PC3 cell proliferation by suppressing osteoclastic bone resorption. In an ex vivo bone organ culture, PC3 cells induced osteoclastic bone resorption when co-cultured with calvarial bone, but TAS-115 effectively suppressed the PC3-induced bone destruction. We found that macrophage colony-stimulating factor-dependent macrophage differentiation and subsequent receptor activator of NF-κB ligand-induced osteoclast formation were largely suppressed by adding TAS-115. The phosphorylation of the macrophage colony-stimulating factor receptor FMS and osteoclast related kinases such as ERK and Akt were also suppressed by the presence of TAS-115. Gene expression profiling showed that FMS expression was only seen in macrophage and in the osteoclast cell lineage. Our study indicates that tyrosine kinase signaling in host pre-osteoclasts/osteoclasts is critical for bone destruction induced by tumor cells and that targeting of MET/VEGF receptor/FMS activity makes it a promising therapeutic candidate for the treatment of prostate cancer patients with bone metastasis.

Original publication

DOI

10.1074/jbc.M116.727875

Type

Journal article

Journal

J Biol Chem

Publication Date

30/09/2016

Volume

291

Pages

20891 - 20899

Keywords

Bone metastasis, HGF/Met, M-CSF/FMS, VEGF/VEGFR, inhibitor, osteoclast, prostate cancer, signaling, tumor microenvironment, tyrosine-protein kinase (tyrosine kinase), Animals, Bone Neoplasms, Bone Resorption, Cell Differentiation, Cell Line, Tumor, Coculture Techniques, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Humans, MAP Kinase Signaling System, Male, Mice, Mice, Nude, Neoplasm Metastasis, Osteoclasts, Prostatic Neoplasms, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-met, Quinolines, Receptor, Macrophage Colony-Stimulating Factor, Receptors, Vascular Endothelial Growth Factor, Thiourea