BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells
BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells
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DOI：
10.1038/sj.onc.1208127
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发表时间：
2004-12-16
期刊：
影响因子：
8
通讯作者：
Miyazono, K
中科院分区：
文献类型：
--
作者：
Miyazaki, H;Watabe, T;Miyazono, K
前列腺癌是男性最常见的癌症之一。多项证据表明骨形态发生蛋白 (BMP) 信号在前列腺癌的产生和进展中发挥重要作用。在本研究中，我们发现 BMP-7 在含有 1% 胎牛血清的培养基中抑制雄激素不敏感的 PC-3 和 DU-145 前列腺癌细胞的增殖，观察到 [H-3] 胸苷掺入减少和细胞数量减少。通过流式细胞术进行的细胞周期分析显示，在 BMP-7 刺激后，G1 期细胞比例增加，随后 S 期和 G2/M 期细胞比例减少。 BMP-7 导致细胞周期蛋白依赖性激酶抑制剂 (CDKI) p21(CIP1/WAF1) 上调，并降低 Cdk2 活性，导致 Rb 蛋白低磷酸化。此外，为了评估 BMP 信号对前列腺肿瘤生长的影响，我们生成了以四环素 (Tet) 调节方式表达组成型活性 BMP I 型受体（组成型活性 (c.a.) 激活素受体样激酶 (ALK)-6）的 PC-3 细胞系。 Tet/多西环素调节的 c.a.ALK-6 表达导致体外细胞增殖受到抑制，并且皮下注射到免疫缺陷小鼠体内的 PC-3 细胞产生的肿瘤尺寸减小。总的来说，这些发现表明 BMP 信号通过诱导 CDKI 抑制前列腺肿瘤细胞的生长和增殖。此外，这是首次报道 BMP 信号传导在降低雄激素不敏感前列腺肿瘤的生长动力学中的作用。
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 [H-3] 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) p21(CIP1/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.