Trk Receptor Inhibition Induces Apoptosis of Proliferating but not Quiescent Human Osteoblasts

摘要: Prostate cancer frequently metastasizes to the skeleton, producing painful osteoblastic lesions, which are associated with significant morbidity and mortality. This bone tropism involves bidirectional paracrine interactions between prostate cells osteoblasts. These enhance cell survival proliferation of Therefore, agents that can induce apoptosis proliferating osteoblasts would be highly advantageous. Previously, we have documented unique pathway for a neurotrophin/Trk receptor autocrine pathway. The indocarbazole compounds, CEP-701 CEP-751, potent inhibitor this Trk signaling thus selectively induces in various vitro vivo models. In study, effects CEP-751 on conditionally immortalized line, hFOB, . At permissive temperature 34°C, these express large T antigen, inducing their continuous proliferation, whereas at 39°C, antigen is degraded stop without undergoing apoptosis. receptors expressed hFOB cells, as determined both by reverse transcription-PCR Western blots. were shown produce nerve growth factor brain-derived neurotrophic but not neurotrophin-3, measured ELISA. osteoblasts, cultured secreted significantly ( P < 0.01) more into medium than 39°C. Because Trk/neurotrophin axis present quiescent i.e. , nonproliferating) 48 h exposure doses viability assessed trypan blue exclusion assays 4′,6-diamidino-2-phenylindole nuclear staining. Cell 34°C dose-dependently decreased compared untreated cells. contrast, even highest concentration (200 nm) did affect trk inhibition-induced cytotoxicity was confirmed using early-passage, normal non-SV40-transformed) human also protein. combined results demonstrate acquire sensitivity inhibition- induced shared normally