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Growth and differentiation factor 9 (GDF-9) induces epithelial–mesenchymal transition in prostate cancer cells

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Abstract

The role of bone morphogenetic proteins in the progression and metastasis of prostate cancer is a topic that has undergone extensive research. This study investigates the role of BMP member growth and differentiation factor 9 (GDF-9) in the progression of this disease. GDF-9 was over-expressed and knocked-down in PC-3 cells, respectively. Furthermore, along with the use of a generated recombinant GDF-9 protein, these cells were then analyzed for any changes in their invasiveness and expression of epithelial–mesenchymal transition (EMT) associated genes. GDF-9 was shown to promote the invasiveness of PC-3 cells together with an induction in the expression of genes including SNAI1, RhoC, ROCK-1, and N-cadherin, while reducing levels of E-cadherin. These expression changes are characteristic of the onset of EMT, and resulted in the cells having a more mesenchymal-like morphology. Treating these cells with activin-like kinase-5 (ALK-5) inhibitor, demonstrated that GDF-9 induced up-regulation of these molecules was ALK-5 dependant. This study shows that in PC-3 cells, GDF-9 signaling via ALK-5, can promote cell invasiveness via a complex network of signaling molecules that work together to trigger the process of EMT, and thereby aid in the aggressiveness and progression of prostate cancer cells.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  2. Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454

    Article  CAS  PubMed  Google Scholar 

  3. Ye L, Lewis-Russell JM, Kynaston H, Jiang WG (2007) Endogenous bone morphogenetic protein-7 controls the motility of prostate cancer cells through regulation of bone morphogenetic protein antagonists. J Urol 178:1086–1091

    Article  CAS  PubMed  Google Scholar 

  4. Lai TH, Fong YC, Fu WM, Yang RS, Tang CH (2008) Osteoblasts-derived BMP-2 enhances the motility of prostate cancer cells via activation of integrins. Prostate 68:1341–1353

    Article  CAS  PubMed  Google Scholar 

  5. Kang MH, Kim JS, Seo JE, Oh SC, Yoo YA (2010) BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Exp Cell Res 316:24–37

    Article  CAS  PubMed  Google Scholar 

  6. Theriault BL, Shepherd TG, Mujoomdar ML, Nachtigal MW (2007) BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells. Carcinogenesis 28:1153–1162

    Article  CAS  PubMed  Google Scholar 

  7. Aaltonen J, Laitinen MP, Vuojolainen K, Jaatinen R, Horelli-Kuitunen N, Seppa L, Louhio H, Tuuri T, Sjoberg J, Butzow R, Hovata O, Dale L, Ritvos O (1999) Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis. J Clin Endocrinol Metab 84:2744–2750

    Article  CAS  PubMed  Google Scholar 

  8. Mazerbourg S, Klein C, Roh J, Kaivo-Oja N, Mottershead DG, Korchynskyi O, Ritvos O, Hsueh AJ (2004) Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5. Mol Endocrinol 18:653–665

    Article  CAS  PubMed  Google Scholar 

  9. Hanavadi S, Martin TA, Watkins G, Mansel RE, Jiang WG (2007) The role of growth differentiation factor-9 (GDF-9) and its analog, GDF-9b/BMP-15, in human breast cancer. Ann Surg Oncol 14:2159–2166

    Article  CAS  PubMed  Google Scholar 

  10. Bokobza SM, Ye L, Kynaston H, Jiang WG (2010) GDF-9 promotes the growth of prostate cancer cells by protecting them from apoptosis. J Cell Physiol 225:529–536

    Article  CAS  PubMed  Google Scholar 

  11. Ye L, Kynaston H, Jiang WG (2008) Bone morphogenetic protein-9 induces apoptosis in prostate cancer cells, the role of prostate apoptosis response-4. Mol Cancer Res 6:1594–1606

    Article  CAS  PubMed  Google Scholar 

  12. Kalluri R, Weinberg RA (2009) The basics of epithelial–mesenchymal transition. J Clin Invest 119:1420–1428

    Article  CAS  PubMed  Google Scholar 

  13. Laitinen M, Vuojolainen K, Jaatinen R, Ketola I, Aaltonen J, Lehtonen E, Heikinheimo M, Ritvos O (1998) A novel growth differentiation factor-9 (GDF-9) related factor is co-expressed with GDF-9 in mouse oocytes during folliculogenesis. Mech Dev 78:135–140

    Article  CAS  PubMed  Google Scholar 

  14. Ma LL, Sun WJ, Wang Z, Zh GY, Li P, Fu SB (2006) Effects of silencing of mutant p53 gene in human lung adenocarcinoma cell line Anip973. J Exp Clin Cancer Res 25:585–592

    CAS  PubMed  Google Scholar 

  15. Zhuang Z, Jian P, Longjiang L, Bo H, Wenlin X (2009) Oral cancer cells with different potential of lymphatic metastasis displayed distinct biologic behaviors and gene expression profiles. J Oral Pathol Med 39:168–175

    Article  PubMed  Google Scholar 

  16. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142

    Article  CAS  PubMed  Google Scholar 

  17. Zavadil J, Bottinger EP (2005) TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24:5764–5774

    Article  CAS  PubMed  Google Scholar 

  18. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968

    Article  CAS  PubMed  Google Scholar 

  19. Gavert N, Ben-Ze’ev A (2008) Epithelial–mesenchymal transition and the invasive potential of tumors. Trends Mol Med 14:199–209

    Article  CAS  PubMed  Google Scholar 

  20. Hauck CR, Hsia DA, Schlaepfer DD (2002) The focal adhesion kinase—a regulator of cell migration and invasion. IUBMB Life 53:115–119

    Article  CAS  PubMed  Google Scholar 

  21. Sakabe M, Sakata H, Matsui H, Ikeda K, Yamagishi T, Nakajima Y (2008) ROCK1 expression is regulated by TGFbeta3 and ALK2 during valvuloseptal endocardial cushion formation. Anat Rec (Hoboken) 291:845–857

    CAS  Google Scholar 

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Acknowledgment

This work was supported by the Dezna Robins Jones Charitable foundation and Cancer Research Wales.

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Authors and Affiliations

  1. Metastasis and Angiogenesis Research Group, Department of Surgery, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK

    Sivan M. Bokobza, Lin Ye, Howard Kynaston & Wen G. Jiang

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  1. Sivan M. Bokobza
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  2. Lin Ye
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  3. Howard Kynaston
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  4. Wen G. Jiang
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Correspondence to Wen G. Jiang.

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Bokobza, S.M., Ye, L., Kynaston, H. et al. Growth and differentiation factor 9 (GDF-9) induces epithelial–mesenchymal transition in prostate cancer cells. Mol Cell Biochem 349, 33–40 (2011). https://doi.org/10.1007/s11010-010-0657-5

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  • DOI: https://doi.org/10.1007/s11010-010-0657-5

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