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lüll SB-431542 and Gleevec inhibit transforming growth factor-beta-induced proliferation of human osteosarcoma cells Matsuyama S; Iwadate M; Kondo M; Saitoh M; Hanyu A; Shimizu K; Aburatani H; Mishima HK; Imamura T; Miyazono K; Miyazawa KCancer Res 2003[Nov]; 63 (22): 7791-8Transforming growth factor-beta (TGF-beta) has growth-stimulating effects on mesenchymal cells and several tumor cell lines. The signaling pathway for this effect is, however, not well understood. We examined how TGF-beta stimulates proliferation of MG63 human osteosarcoma cells. Two distinct type I receptors for TGF-beta, ALK-1 and ALK-5, were expressed and functional in MG63 cells. Of these two receptors, ALK-5 appears to be responsible for the growth stimulation because expression of constitutively active ALK-5, but not ALK-1, stimulated proliferation of MG63 cells. SB-431542 (0.3 microM), a novel inhibitor of ALK4/5/7 kinase, suppressed TGF-beta-induced growth stimulation. DNA microarray analysis as well as quantitative real-time PCR analysis of RNAs from TGF-beta-treated cells demonstrated that several growth factors, including platelet-derived growth factor AA, were induced in response to TGF-beta in MG63 cells. Gleevec (1 microM) as well as AG1296 (5 microM) inhibited TGF-beta-induced growth stimulation of MG63 cells, suggesting that platelet-derived growth factor AA was mainly responsible for the growth-stimulatory effect of TGF-beta. We also examined the mechanisms of perturbation of growth-suppressing signaling in MG63 cells. We found that expression of c-Myc, which is down-regulated by TGF-beta in many other cells, was up-regulated in MG63 cells, suggesting that up-regulation of c-Myc expression may be the mechanism canceling growth-suppressing signaling of TGF-beta in MG63 cells.|Activin Receptors, Type I/biosynthesis/physiology[MESH]|Activin Receptors, Type II[MESH]|Animals[MESH]|Antineoplastic Agents/*pharmacology[MESH]|Benzamides/*pharmacology[MESH]|Bone Neoplasms/drug therapy/genetics/metabolism/*pathology[MESH]|Cell Division/drug effects/physiology[MESH]|Cell Line, Tumor[MESH]|Cyclin-Dependent Kinase Inhibitor p21[MESH]|Cyclins/biosynthesis/genetics[MESH]|Dioxoles/*pharmacology[MESH]|Drug Interactions[MESH]|Gene Expression Regulation, Neoplastic/drug effects[MESH]|Humans[MESH]|Imatinib Mesylate[MESH]|Mice[MESH]|NIH 3T3 Cells[MESH]|Oligonucleotide Array Sequence Analysis[MESH]|Osteosarcoma/drug therapy/genetics/metabolism/*pathology[MESH]|Piperazines/*pharmacology[MESH]|Protein Serine-Threonine Kinases[MESH]|Proto-Oncogene Proteins c-myc/biosynthesis/genetics[MESH]|Pyrimidines/*pharmacology[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/biosynthesis/physiology[MESH]|Signal Transduction/physiology[MESH]|Transforming Growth Factor beta/*antagonists & inhibitors/pharmacology/physiology[MESH]|Up-Regulation/drug effects[MESH] |