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Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts

Oncogene volume 29, pages 3196–3207 (2010)Cite this article

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Abstract

Dasatinib, a dual Src family kinase and Abl inhibitor, is being tested clinically for the treatment of prostate cancer bone metastasis. Bidirectional interactions between osteoblasts and prostate cancer cells are critical in the progression of prostate cancer in bone, but the effect of dasatinib on osteoblasts is unknown. We found that dasatinib inhibited proliferation of primary mouse osteoblasts isolated from mouse calvaria and the immortalized MC3T3-E1 cell line. In calvarial osteoblasts from Col-luc transgenic mice carrying osteoblast-specific Col1α1 promoter reporter, luciferase activity was inhibited. Dasatinib also inhibited fibroblast growth factor-2-induced osteoblast proliferation, but strongly promoted osteoblast differentiation, as reflected by stimulation of alkaline phosphatase activity, osteocalcin secretion and osteoblast mineralization. To determine how dasatinib blocks proliferative signaling in osteoblasts, we analyzed the expression of a panel of tyrosine kinases, including Src, Lyn, Fyn, Yes and Abl, in osteoblasts. In the Src family kinases, only Src was activated at a high level. Abl was expressed at a low level in osteoblasts. Phosphorylation of Src-Y419 or Abl-Y245 was inhibited by dasatinib treatment. Knockdown of either Src or Abl by lenti-shRNA in osteoblasts enhances osteoblast differentiation, suggesting that dasatinib enhances osteoblast differentiation through inhibition of both Src and Abl.

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References

  • Araujo J, Logothetis C . (2009). Targeting Src signaling in metastatic bone disease. Int J Cancer 124: 1–6.

    Article  CAS  Google Scholar 

  • Aubin JE . (1998). Advances in the osteoblast lineage. Biochem Cell Biol 76: 899–910.

    Article  CAS  Google Scholar 

  • Autzen P, Robson CN, Bjartell A, Malcolm AJ, Johnson MI, Neal DE et al. (1998). Bone morphogenetic protein 6 in skeletal metastases from prostate cancer and other common human malignancies. Br J Cancer 78: 1219–1223.

    Article  CAS  Google Scholar 

  • Bellows CG, Aubin JE . (1989). Determination of numbers of osteoprogenitors present in isolated fetal rat calvaria cells in vitro. Dev Biol 133: 8–13.

    Article  CAS  Google Scholar 

  • Berman E, Nicolaides M, Maki RG, Fleisher M, Chanel S, Scheu K et al. (2006). Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 354: 2006–2013.

    Article  CAS  Google Scholar 

  • Bhargava U, Bar-Lev M, Bellows CG, Aubin JE . (1988). Ultrastructural analysis of bone nodules formed in vitro by isolated fetal rat calvaria cells. Bone 9: 155–163.

    Article  CAS  Google Scholar 

  • Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR . (1992). Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest 90: 1622–1627.

    Article  CAS  Google Scholar 

  • Brownlow N, Mol C, Hayford C, Ghaem-Maghami S, Dibb NJ . (2009). Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor. Leukemia 23: 590–594.

    Article  CAS  Google Scholar 

  • Canalis E, Centrella M, McCarthy T . (1988). Effects of basic fibroblast growth factor on bone formation in vitro. J Clin Invest 81: 1572–1577.

    Article  CAS  Google Scholar 

  • Cartwright CA, Kamps MP, Meisler AI, Pipas JM, Eckhart W . (1989). pp60c-src activation in human colon carcinoma. J Clin Invest 83: 2025–2033.

    Article  CAS  Google Scholar 

  • Cartwright CA, Meisler AI, Eckhart W . (1990). Activation of the pp60c-src protein kinase is an early event in colonic carcinogenesis. Proc Natl Acad Sci USA 87: 558–562.

    Article  CAS  Google Scholar 

  • Chen N, Ye XC, Chu K, Navone NM, Sage EH, Yu-Lee LY et al. (2007). A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells. Cancer Res 67: 6544–6548.

    Article  CAS  Google Scholar 

  • Dai J, Keller J, Zhang J, Lu Y, Yao Z, Keller ET . (2005). Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Res 65: 8274–8285.

    Article  CAS  Google Scholar 

  • Debiais F, Lemonnier J, Hay E, Delannoy P, Caverzasio J, Marie PJ . 2001). Fibroblast growth factor-2 (FGF-2) increases N-cadherin expression through protein kinase C and Src-kinase pathways in human calvaria osteoblasts. J Cell Biochem 81: 68–81.

    Article  CAS  Google Scholar 

  • Dorkin TJ, Robinson MC, Marsh C, Bjartell A, Neal DE, Leung HY . (1999a). FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease. Oncogene 18: 2755–2761.

    Article  CAS  Google Scholar 

  • Dorkin TJ, Robinson MC, Marsh C, Neal DE, Leung HY . (1999b). aFGF immunoreactivity in prostate cancer and its co-localization with bFGF and FGF8. J Pathol 189: 564–569.

    Article  CAS  Google Scholar 

  • Fakhry A, Ratisoontorn C, Vedhachalam C, Salhab I, Koyama E, Leboy P et al. (2005). Effects of FGF-2/-9 in calvarial bone cell cultures: differentiation stage-dependent mitogenic effect, inverse regulation of BMP-2 and noggin, and enhancement of osteogenic potential. Bone 36: 254–266.

    Article  CAS  Google Scholar 

  • Franceschi RT, Iyer BS . (1992). Relationship between collagen synthesis and expression of the osteoblast phenotype in MC3T3-E1 cells. J Bone Miner Res 7: 235–246.

    Article  CAS  Google Scholar 

  • Globus RK, Patterson-Buckendahl P, Gospodarowicz D . (1988). Regulation of bovine bone cell proliferation by fibroblast growth factor and transforming growth factor beta. Endocrinology 123: 98–105.

    Article  CAS  Google Scholar 

  • Hannon RA, Clack G, Rimmer M, Swaisland A, Lockton JA, Finkelman RD et al. (2009). Effects of the Src kinase inhibitor saracatinib (AZD 0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple ascending dose phase I trial. J Bone Miner Res (e-pub ahead of print 14 December 2009).

  • Ito H, Gardner-Thorpe J, Zinner MJ, Ashley SW, Whang EE . (2003). Inhibition of tyrosine kinase Src suppresses pancreatic cancer invasiveness. Surgery 134: 221–226.

    Article  Google Scholar 

  • Jacob K, Webber M, Benayahu D, Kleinman HK . (1999). Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone. Cancer Res 59: 4453–4457.

    CAS  Google Scholar 

  • Kopetz S, Shah AN, Gallick GE . (2007). Src continues aging: current and future clinical directions. Clin Cancer Res 13: 7232–7236.

    Article  CAS  Google Scholar 

  • Koreckij T, Nguyen H, Brown LG, Yu EY, Vessella RL, Corey E . (2009). Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br J Cancer 101: 263–268.

    Article  CAS  Google Scholar 

  • Li B, Boast S, de los Santos K, Schieren I, Quiroz M, Teitelbaum SL et al. (2000). Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nat Genet 24: 304–308.

    Article  CAS  Google Scholar 

  • Li Z, Mathew P, Yang J, Starbuck M-W, Zurita AJ, Liu J et al. (2008). Androgen receptor-negative human prostate cancer cells induce osteogenesis through FGF9-mediated mechanisms. J Clin Invest 118: 2697–2710.

    Article  CAS  Google Scholar 

  • Lin S-H, Cheng CJ, Lee Y-C, Ye X, Tsai W-W, Kim J et al. (2008). A 45-kDa ErbB3 secreted by prostate cancer cells promotes bone formation. Oncogene 27: 5195–5203.

    Article  CAS  Google Scholar 

  • Logothetis C, Lin S-H . (2005). Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer 5: 21–28.

    Article  CAS  Google Scholar 

  • Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K et al. (2004). Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47: 6658–6661.

    Article  CAS  Google Scholar 

  • Lowe C, Yoneda T, Boyce BF, Chen H, Mundy GR, Soriano P . (1993). Osteopetrosis in Src-deficient mice is due to an autonomous defect of osteoclasts. Proc Natl Acad Sci USA 90: 4485–4489.

    Article  CAS  Google Scholar 

  • Marzia M, Sims NA, Voit S, Migliaccio S, Taranta A, Bernardini S et al. (2000). Decreased c-Src expression enhances osteoblast differentiation and bone formation. J Cell Biol 151: 311–320.

    Article  CAS  Google Scholar 

  • Masuda H, Fukabori Y, Nakano K, Takezawa Y, CSuzuki T, Yamanaka H . (2003). Increased expression of bone morphogenetic protein-7 in bone metastatic prostate cancer. Prostate 54: 268–274.

    Article  CAS  Google Scholar 

  • Mayahara H, Ito T, Nagai H, Miyajima H, Tsukuda R, Taketomi S et al. (1993). in vivo stimulation of endosteal bone formation by basic fibroblast growth factor in rats. Growth Factors 9: 73–80.

    Article  CAS  Google Scholar 

  • McCarthy TL, Centrella M, Canalis E . (1989). Effects of fibroblast growth factors on deoxyribonucleic acid and collagen synthesis in rat parietal bone cells. Endocrinology 125: 2118–2126.

    Article  CAS  Google Scholar 

  • Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R et al. (2005). Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 65: 9185–9189.

    Article  CAS  Google Scholar 

  • Nelson JB, Hedican SP, George AH, Reddi AH, Piantadosi S, Eisenberger MA et al. (1995). Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1: 944–949.

    Article  CAS  Google Scholar 

  • Nelson JB, Nguyen SH, Wu-Wong JR, Opgenorth TJ, Dixon DB, Chung LW et al. (1999). New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade. Urology 53: 1063–1069.

    Article  CAS  Google Scholar 

  • Park SI, Zhang J, Phillips KA, Araujo JC, Najjar AM, Volgin AY et al. (2008). Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res 68: 3323–3333.

    Article  CAS  Google Scholar 

  • Rossert J, Eberspaecher H, de Crombrugghe B . (1995). Separate cis-acting DNA elements of the mouse pro-alpha 1(I) collagen promoter direct expression of reporter genes to different type I collagen-producing cells in transgenic mice. J Cell Biol 129: 1421–1432.

    Article  CAS  Google Scholar 

  • Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL . (2004). Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305: 399–401.

    Article  CAS  Google Scholar 

  • Shor AC, Keschman EA, Lee FY, Muro-Cacho C, Letson GD, Trent JC et al. (2007). Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival. Cancer Res 67: 2800–2808.

    Article  CAS  Google Scholar 

  • Soriano P, Montgomery C, Geske R, Bradley A . (1991). Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64: 693–702.

    Article  CAS  Google Scholar 

  • Stein GS, Lian JB . (1993). Molecular mechanisms mediating proliferation/differentiation interrelationships during progressive development of the osteoblast phenotype. Endocr Rev 14: 424–442.

    Article  CAS  Google Scholar 

  • Summy JM, Gallick GE . (2003). Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev 22: 337–358.

    Article  CAS  Google Scholar 

  • Talamonti MS, Roh MS, Curley SA, Gallick GE . (1993). Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. J Clin Invest 91: 53–60.

    Article  CAS  Google Scholar 

  • Trevino JG, Summy JM, Lesslie DP, Parikh NU, Hong DS, Lee FY et al. (2006). Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol 168: 962–972.

    Article  CAS  Google Scholar 

  • Vakar-Lopez F, Cheng C-J, Kim J, Shi GG, Troncoso P, Tu S-M et al. (2004). Up-regulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow. J Pathol 203: 688–695.

    Article  CAS  Google Scholar 

  • Ye XC, Choueiri M, Tu SM, Lin SH . (2007). Biology and clinical management of prostate cancer bone metastasis. Front Biosci 12: 3273–3286.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Karen Philips for editing the paper. This study was supported by National Institutes of Health Grants CA111479 (SH Lin), P50 CA140388 (SH Lin, GE Gallick) and DK53176 (LY Yu-Lee), and by the Prostate Cancer Foundation (SH Lin).

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Authors and Affiliations

  1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y-C Lee, C-F Huang, X Ye & S-H Lin

  2. Department of Pharmacy at National Taiwan University Hospital, Graduate Institute of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan

    C-F Huang

  3. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Murshed, K Chu, J C Araujo, G E Gallick & S-H Lin

  4. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    B deCrombrugghe

  5. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    L-Y Yu-Lee

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  1. Y-C Lee
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Correspondence to S-H Lin.

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Lee, YC., Huang, CF., Murshed, M. et al. Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts. Oncogene 29, 3196–3207 (2010). https://doi.org/10.1038/onc.2010.73

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