erbstatin and Osteosarcoma

[3H]Thymidine (TdR) incorporation by human osteosarcoma cell line MG-63 was significantly stimulated at as early as 3 h after the addition of either TIMP-1 or TIMP-2 alone. Maximum stimulation was attained at a concentration of either 20 ng/ml (0.71 nM) TIMP-1 or 1.0 ng/ml (46 pM) TIMP-2. Tyrosine kinase inhibitors such as genistein, erbstatin, and herbimycin A almost completely inhibited the [3H]TdR incorporation stimulated by either of the TIMPs. However, essentially no effect was observed with H-89, H-7, bisindolylmaleimide and K-252a. These inhibition studies suggest a crucial role for tyrosine kinase in the signal transduction of TIMPs. Phosphotyrosine-containing proteins were significantly elevated by the treatment with both TIMPs. We also found that either TIMP stimulated an increase in mitogen-activated protein (MAP) kinase activity, suggesting that MAP kinase plays a role in TIMP-dependent growth signaling.

Topics: Benzoquinones; Calcium-Calmodulin-Dependent Protein Kinases; DNA; Enzyme Activation; Genistein; Glycoproteins; Humans; Hydroquinones; Isoflavones; Lactams, Macrocyclic; Mitogen-Activated Protein Kinase 1; Osteosarcoma; Phosphorylation; Protease Inhibitors; Protein-Tyrosine Kinases; Proteins; Quinones; Rifabutin; Signal Transduction; Thymidine; Time Factors; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinases; Tritium; Tumor Cells, Cultured; Tyrosine