Bone morphogenetic protein-6 induces castration resistance in prostate cancer cells through tumor infiltrating macrophages
Bone morphogenetic protein-6 induces castration resistance in prostate cancer cells through tumor infiltrating macrophages
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DOI：
10.1111/cas.12206
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发表时间：
2013-08-01
期刊：
影响因子：
5.7
通讯作者：
Kim, Isaac Y.
中科院分区：
文献类型：
--
作者：
Lee, Geun Taek;Jung, Yeon Suk;Kim, Isaac Y.
骨形态发生蛋白（BMP）是一种多效性生长因子，与炎症和前列腺癌（CaP）进展有关。我们研究了BMP-6在巨噬细胞和去势抵抗性前列腺癌中的潜在作用。当雄激素应答的鼠（P 8）和人（LNCaP）CaP细胞系与巨噬细胞在双氢睾酮存在下共培养时，BMP-6显著增加雄激素应答启动子活性和细胞计数。随后的研究表明，BMP-6增加雄激素受体（AR）的mRNA和蛋白的表达水平在CaP细胞系中，只有在巨噬细胞的存在。同时，AR拮抗剂比卡鲁胺和MDV 3100部分或完全阻断BMP-6诱导的巨噬细胞介导的CaP细胞雄激素超敏反应。在CaP/巨噬细胞共培养物中用中和抗体消除白细胞介素-6信号传导抑制了CaP细胞中BMP-6介导的AR上调。使用具有四环素诱导的BMP-6表达的P8细胞，体内BMP-6的诱导导致对去势的显著抗性。然而，在用氯膦酸盐脂质体去除巨噬细胞后，这种抗性被阻断。BMP-6通过巨噬细胞来源的白细胞介素-6增加AR的表达诱导去势抵抗。
Bone morphogenetic protein (BMP) is a pleiotropic growth factor that has been implicated in inflammation and prostate cancer (CaP) progression. We investigated the potential role of BMP-6 in the context of macrophages and castration-resistant prostate cancer. When the androgen-responsive murine ( P 8) and human (LNCaP) CaP cell lines were cocultured with macrophages in the presence of dihydrotestosterone, BMP-6 increased androgen-responsive promoter activity and cell count significantly. Subsequent studies revealed that BMP-6 increased the expression level of androgen receptor (AR) mRNA and protein in CaP cell lines only in the presence of macrophages. Simultaneously, the AR antagonists bicalutamide and MDV3100 partially or completely blocked BMP-6-induced macrophage-mediated androgen hypersensitivity in CaP cells. Abolishing interleukin-6 signaling with neutralizing antibody in CaP/macrophage cocultures inhibited the BMP-6-mediated AR upregulation in CaP cells. Using P 8 cells with a tetracycline-inducible expression of BMP-6, the induction of BMP-6 in vivo resulted in a significant resistance to castration. However, this resistance was blocked after the removal of macrophages with clodronate liposomes. BMP-6 induces castration resistance by increasing the expression of AR through macrophage-derived interleukin-6.