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  • Original Paper
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BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells

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.

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Abbreviations

ALK:

activin receptor-like kinase

BMP:

bone morphogenetic protein

c.a.:

constitutively active

Co-Smad:

common-partner Smad

Dox:

doxycycline

FBS:

fetal bovine serum

R-Smad:

receptor-regulated Smad

Tet:

tetracycline

TGF:

transforming growth factor

tTA:

tetracycline transactivator

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Acknowledgements

We thank T Era for providing pCAG 20-1 and pUHD10-3 Puro vectors and our colleagues and S Horie for suggestions and discussion. This research was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Science, Sports, and Technology of Japan.

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Correspondence to Kohei Miyazono.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Miyazaki, H., Watabe, T., Kitamura, T. et al. BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells. Oncogene 23, 9326–9335 (2004). https://doi.org/10.1038/sj.onc.1208127

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