BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells
Open Access
- 8 November 2004
- journal article
- research article
- Published by Springer Nature in Oncogene
- Vol. 23 (58) , 9326-9335
- https://doi.org/10.1038/sj.onc.1208127
Abstract
Prostate cancer is one of the most common cancers in men. Several lines of evidence have suggested that bone morphogenetic protein (BMP) signals play important roles in the generation and progression of prostate cancers. In the present study, we show that BMP-7 inhibits the proliferation of androgen-insensitive PC-3 and DU-145 prostate cancer cells in a medium containing 1% fetal bovine serum, observed as decreased incorporation of [3H]thymidine and decreased cell number. Cell cycle analysis by flow cytometry showed an increased fraction of cells in the G1 phase and subsequent decrease in both S and G2/M phase after BMP-7 stimulation. BMP-7 caused an upregulation of the cyclin-dependent kinase inhibitor (CDKI) p21CIP1/WAF1, and decreased the activity of Cdk2, leading to hypophosphorylation of Rb proteins. Furthermore, in order to evaluate the impact of BMP signals on prostate tumor growth, we generated the PC-3 cell lines expressing a constitutively active BMP type I receptor (constitutively active (c.a.) activin receptor-like kinase (ALK)-6) in a tetracycline (Tet)-regulated manner. Tet/doxycycline-regulated expression of c.a.ALK-6 resulted in the inhibition of in vitro cell proliferation and reduction of the size of tumors derived from the PC-3 cells subcutaneously injected into immune-deficient mice. Collectively, these findings suggest that BMP signals inhibit growth and proliferation of prostate tumor cells through induction of CDKI. Furthermore, this is the first report of a role for BMP signaling in reducing growth kinetics of androgen-insensitive prostate tumors.Keywords
This publication has 31 references indexed in Scilit:
- Bone morphogenetic protein signaling in prostate cancer cell linesJournal of Cellular Biochemistry, 2003
- Increased expression of bone morphogenetic protein‐7 in bone metastatic prostate cancerThe Prostate, 2003
- SB-431542 Is a Potent and Specific Inhibitor of Transforming Growth Factor-β Superfamily Type I Activin Receptor-Like Kinase (ALK) Receptors ALK4, ALK5, and ALK7Molecular Pharmacology, 2002
- Identification of Novel Inhibitors of the Transforming Growth Factor β1 (TGF-β1) Type 1 Receptor (ALK5)Journal of Medicinal Chemistry, 2002
- BMP-7-Induced Cell Cycle Arrest of Anaplastic Thyroid Carcinoma Cells via p21CIP1 and p27KIP1Biochemical and Biophysical Research Communications, 2001
- Cancer Statistics, 2001CA: A Cancer Journal for Clinicians, 2001
- Bone Morphogenetic Protein-2 Blocks MDA MB 231 Human Breast Cancer Cell Proliferation by Inhibiting Cyclin-Dependent Kinase-Mediated Retinoblastoma Protein PhosphorylationBiochemical and Biophysical Research Communications, 2000
- Truncated Type II Receptor for BMP-4 Induces Secondary Axial Structures in Xenopus EmbryosBiochemical and Biophysical Research Communications, 1995
- Morphometric Evidence for Bone Resorption and Replacement in Prostate CancerBritish Journal of Urology, 1991
- The retinoblastoma protein is phosphorylated during specific phases of the cell cycleCell, 1989