Endogenous Bone Morphogenetic Protein-7 Controls the Motility of Prostate Cancer Cells Through Regulation of Bone Morphogenetic Protein Antagonists

No AccessJournal of UrologyInvestigative urology1 Sep 2007Endogenous Bone Morphogenetic Protein-7 Controls the Motility of Prostate Cancer Cells Through Regulation of Bone Morphogenetic Protein Antagonistsis accompanied byBone Morphogenetic Proteins and Prostate Cancer: Evolving Complexitiesis companion ofSerum Bone Turnover Markers (PINP and ICTP) for the Early Detection of Bone Metastases in Patients With Prostate Cancer: A Longitudinal Approach Lin Ye, Jonathan M. Lewis-Russell, Howard Kynaston, and Wen G. Jiang Lin YeLin Ye , Jonathan M. Lewis-RussellJonathan M. Lewis-Russell , Howard KynastonHoward Kynaston , and Wen G. JiangWen G. Jiang View All Author Informationhttps://doi.org/10.1016/j.juro.2007.05.003AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We investigated the effect of manipulating endogenous BMP-7 expression on the invasion and motility of prostate cancer cells and the resulting effect on its antagonists using a ribozyme transgene. Materials and Methods: A hammerhead ribozyme transgene was synthesized and cloned into a mammalian expression vector (pcDNA3.1/nt-GFP-TOPO). PC-3 cells (American Type Culture Collection, Manassas, Virginia) were transfected with the ribozyme transgene (PC-3ΔBMP7) or with an empty plasmid (PC-3pcDNA/GFP) by electroporation. Invasion and motility were accessed by in vitro invasion and motility assays. Results: The ribozyme decreased BMP-7 expression at the mRNA and protein levels in PC-3 cells. Invasive potential was significantly increased following the loss of BMP-7 expression. The mean ± SD invading cell number for PC-3ΔBMP7 was 231.3 ± 28.6 vs 7.1 ± 4.4 for the WT cell line PC-3WT and 2.7 ± 2 for PC-3pcDNA/GFP (each p <0.001). BMP-7 knockdown in PC-3 cells significantly increased motility with a migrating cell number for PC-3ΔBMP7 of 24 ± 7.5 compared with 10.2 ± 4.5 for PC-3WT and 11.3 ± 7.5 for PC-3pcDNA/GFP (p <0.01 and 0.011, respectively). The change in motility was seen together with changes in the cellular location of paxillin and focal adhesion kinase (p125FAK). Interestingly the loss of BMP-7 resulted in decreased noggin and follistatin expression. Conclusions: The loss of endogenous BMP-7 from prostate cancer cells is associated with increased invasiveness and motility, which appears to be facilitated by changes in the level of the BMP antagonists noggin and follistatin. Endogenous BMP-7 has an important role in controlling noggin and follistatin expression. References 1 : Pattern of prostate cancer metastasis to the vertebral column. Prostate1994; 25: 141. Google Scholar 2 : Bone morphogenetic protein-6 expression in normal and malignant prostate. World J Urol1995; 13: 337. Google Scholar 3 : Epigenetic regulation of human bone morphogenetic protein 6 gene expression in prostate cancer. J Bone Miner Res2001; 16: 487. Google Scholar 4 : Expression of bone morphogenetic protein messenger RNAs by normal rat and human prostate and prostate cancer cells. Prostate1994; 24: 204. Google Scholar 5 : Expression of bone morphogenetic protein-7 (BMP-7) in human prostate. Prostate2004; 59: 101. Google Scholar 6 : Increased expression of bone morphogenetic protein-7 in bone metastatic prostate cancer. Prostate2003; 54: 268. Google Scholar 7 : BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells. Oncogene2004; 23: 9326. Google Scholar 8 : Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells. Cancer Res2005; 65: 5769. Google Scholar 9 : Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone2006; 38: 154. Google Scholar 10 : Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res2003; 31: 3406. Google Scholar 11 : Smooth muscle-derived factor stimulates mobility of human tumor cells. Invas Metast1990; 10: 49. Google Scholar 12 : Targeting matrilysin and its impact on tumor growth in vivo: the potential implications in breast cancer therapy. Clin Cancer Res2005; 11: 6012. Google Scholar 13 : Hepatocyte growth factor/scatter factor decreases the expression of occludin and transendothelial resistance (TER) and increases paracellular permeability in human vascular endothelial cells. J Cell Physiol1999; 181: 319. Google Scholar 14 : Bone morphogenetic protein 7 protects prostate cancer cells from stress-induced apoptosis via both Smad and c-Jun NH2-terminal kinase pathways. Cancer Res2006; 66: 4285. Google Scholar 15 : Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone2006; 38: 154. Google Scholar 16 : Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts. J Clin Invest1998; 102: 2106. Google Scholar 17 : Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev2003; 24: 218. Google Scholar 18 : Testing the antagonistic effect of follistatin on BMP family members in ovine granulosa cells. Reprod Nutr Dev2005; 45: 419. Google Scholar 19 : Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer. J Bone Miner Res2005; 20: 2189. Google Scholar 20 : Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Res2005; 65: 8274. Google Scholar Metastasis and Angiogenesis Research Group, Department of Surgery, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom© 2007 by American Urological AssociationFiguresReferencesRelatedDetailsCited ByYe L, Kynaston H and Jiang W (2018) Bone Morphogenetic Protein-10 Suppresses the Growth and Aggressiveness of Prostate Cancer Cells Through a Smad Independent PathwayJournal of Urology, VOL. 181, NO. 6, (2749-2759), Online publication date: 1-Jun-2009.Related articlesJournal of UrologyJul 16, 2007, 12:00:00 AMBone Morphogenetic Proteins and Prostate Cancer: Evolving ComplexitiesJournal of UrologyJul 16, 2007, 12:00:00 AMSerum Bone Turnover Markers (PINP and ICTP) for the Early Detection of Bone Metastases in Patients With Prostate Cancer: A Longitudinal Approach Volume 178Issue 3September 2007Page: 1086-1091 Advertisement Copyright & Permissions© 2007 by American Urological AssociationKeywordsfollistatinnoggin proteinbone morphogenetic proteinsprostatic neoplasmsprostateAcknowledgmentsDedicated to Dr. Gaynor Davies (1967 to 2006), who assisted with anti-BMP-7 ribozyme construction. Professor Norman Maitland, University of York, United Kingdom provided PNT-1A and PNT-2C2 cells.MetricsAuthor Information Lin Ye More articles by this author Jonathan M. Lewis-Russell More articles by this author Howard Kynaston More articles by this author Wen G. Jiang More articles by this author Expand All Advertisement PDF DownloadLoading ...