This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsuyama, S. Articles by Miyazawa, K. Search for Related Content PubMed PubMed Citation Articles by Matsuyama, S. Articles by Miyazawa, K.

SB-431542 and Gleevec Inhibit Transforming Growth Factor-ß-Induced Proliferation of Human Osteosarcoma Cells

¹ Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo;
² Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo;
³ Department of Ophthalmology, Hiroshima University School of Medicine, Hiroshima;
⁴ Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma;
⁵ Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan

Transforming growth factor-ß (TGF-ß) 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-ß stimulates proliferation of MG63 human osteosarcoma cells. Two distinct type I receptors for TGF-ß, 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 µM), a novel inhibitor of ALK4/5/7 kinase, suppressed TGF-ß-induced growth stimulation. DNA microarray analysis as well as quantitative real-time PCR analysis of RNAs from TGF-ß-treated cells demonstrated that several growth factors, including platelet-derived growth factor AA, were induced in response to TGF-ß in MG63 cells. Gleevec (1 µM) as well as AG1296 (5 µM) inhibited TGF-ß-induced growth stimulation of MG63 cells, suggesting that platelet-derived growth factor AA was mainly responsible for the growth-stimulatory effect of TGF-ß. 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-ß 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-ß in MG63 cells.

This article has been cited by other articles:

				M. Labelle, H. J. Schnittler, D. E. Aust, K. Friedrich, G. Baretton, D. Vestweber, and G. Breier Vascular Endothelial Cadherin Promotes Breast Cancer Progression via Transforming Growth Factor {beta} Signaling Cancer Res., March 1, 2008; 68(5): 1388 - 1397. [Abstract] [Full Text] [PDF]

				H. J. You, M. W. Bruinsma, T. How, J. H. Ostrander, and G. C. Blobe The type III TGF- receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation Carcinogenesis, December 1, 2007; 28(12): 2491 - 2500. [Abstract] [Full Text] [PDF]

				S. Ehata, A. Hanyu, M. Hayashi, H. Aburatani, Y. Kato, M. Fujime, M. Saitoh, K. Miyazawa, T. Imamura, and K. Miyazono Transforming Growth Factor-{beta} Promotes Survival of Mammary Carcinoma Cells through Induction of Antiapoptotic Transcription Factor DEC1 Cancer Res., October 15, 2007; 67(20): 9694 - 9703. [Abstract] [Full Text] [PDF]

				N. I. Chaudhary, G. J. Roth, F. Hilberg, J. Muller-Quernheim, A. Prasse, G. Zissel, A. Schnapp, and J. E. Park Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis Eur. Respir. J., May 1, 2007; 29(5): 976 - 985. [Abstract] [Full Text] [PDF]

				P. Corsino, B. Davis, M. Law, A. Chytil, E. Forrester, P. Norgaard, N. Teoh, and B. Law Tumors Initiated by Constitutive Cdk2 Activation Exhibit Transforming Growth Factor {beta} Resistance and Acquire Paracrine Mitogenic Stimulation during Progression Cancer Res., April 1, 2007; 67(7): 3135 - 3144. [Abstract] [Full Text] [PDF]

				M. Sakuma, K. Hatsushika, K. Koyama, R. Katoh, T. Ando, Y. Watanabe, M. Wako, M. Kanzaki, S. Takano, H. Sugiyama, et al. TGF-{beta} type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody Int. Immunol., February 1, 2007; 19(2): 117 - 126. [Abstract] [Full Text] [PDF]

				N. P. Agaram, P. Besmer, G. C. Wong, T. Guo, N. D. Socci, R. G. Maki, D. DeSantis, M. F. Brennan, S. Singer, R. P. DeMatteo, et al. Pathologic and Molecular Heterogeneity in Imatinib-Stable or Imatinib-Responsive Gastrointestinal Stromal Tumors Clin. Cancer Res., January 1, 2007; 13(1): 170 - 181. [Abstract] [Full Text] [PDF]

				Y.-G. Chen, Q. Wang, S.-L. Lin, C. D. Chang, J. Chung, and S.-Y. Ying Activin Signaling and Its Role in Regulation of Cell Proliferation, Apoptosis, and Carcinogenesis. Experimental Biology and Medicine, May 1, 2006; 231(5): 534 - 544. [Abstract] [Full Text] [PDF]

				A. Suzuki, G.-i. Kusakai, Y. Shimojo, J. Chen, T. Ogura, M. Kobayashi, and H. Esumi Involvement of Transforming Growth Factor-{beta}1 Signaling in Hypoxia-induced Tolerance to Glucose Starvation J. Biol. Chem., September 9, 2005; 280(36): 31557 - 31563. [Abstract] [Full Text] [PDF]

				K. Mimura, K. Kono, M. Hanawa, M. Kanzaki, A. Nakao, A. Ooi, and H. Fujii Trastuzumab-Mediated Antibody-Dependent Cellular Cytotoxicity against Esophageal Squamous Cell Carcinoma Clin. Cancer Res., July 1, 2005; 11(13): 4898 - 4904. [Abstract] [Full Text] [PDF]

				M. D. Hjelmeland, A. B. Hjelmeland, S. Sathornsumetee, E. D. Reese, M. H. Herbstreith, N. J. Laping, H. S. Friedman, D. D. Bigner, X.-F. Wang, and J. N. Rich SB-431542, a small molecule transforming growth factor-{beta}-receptor antagonist, inhibits human glioma cell line proliferation and motility Mol. Cancer Ther., June 1, 2004; 3(6): 737 - 745. [Abstract] [Full Text] [PDF]