Osteoblasts Generate Testosterone From DHEA and Activate Androgen Signaling in Prostate Cancer Cells.
Osteoblasts Generate Testosterone From DHEA and Activate Androgen Signaling in Prostate Cancer Cells.
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成骨细胞从DHEA产生睾丸激素并激活前列腺癌细胞中的雄激素信号。
DOI：
10.1002/jbmr.4313
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Clines GA
中科院分区：
文献类型：
--
作者：
Moon HH;Clines KL;O'Day PJ;Al-Barghouthi BM;Farber EA;Farber CR;Auchus RJ;Clines GA
骨转移是前列腺癌的并发症，高达90%的男性患有晚期疾病。减少雄激素暴露的疗法仍然处于治疗的最前沿。然而，大多数前列腺癌转变为减少睾丸雄激素作用变得无效的状态。这种转变的常见机制是使用肾上腺雄激素前体脱氢表雄酮（DHEA）通过3β-和17β-羟基类固醇脱氢酶（3βHSD和17βHSD）的酶促转化在肿瘤内产生睾酮（T）。鉴于前列腺癌在骨中形成母细胞转移的能力，我们假设成骨细胞可能是雄激素合成的来源。鼠成骨细胞和人骨的RNA表达分析证实，至少有一种3βHSD和17βHSD酶亚型表达，表明成骨细胞能够从肾上腺DHEA产生雄激素。用100 nM和1 μM DHEA或溶剂对照处理小鼠成骨细胞。从这些成骨细胞的条件培养基进行了测定中间和活性雄激素的液相色谱-串联质谱。随着脱氢表雄酮的消耗，雄激素中间体雄烯二醇和雄烯二酮产生，随后转化为T。DHEA处理的成骨细胞的条件培养基增加雄激素受体（AR）信号传导、PSA产生和雄激素敏感性前列腺癌细胞系C4-2B和LNCaP的细胞数量。DHEA没有诱导成骨细胞中的AR信号，尽管在这种细胞类型中有AR表达。我们描述了一个未报道的功能，成骨细胞作为一个来源的T，这是特别相关的雄激素反应性转移性前列腺癌侵入骨。
Bone metastasis is a complication of prostate cancer in up to 90% of men afflicted with advanced disease. Therapies that reduce androgen exposure remain at the forefront of treatment. However, most prostate cancers transition to a state whereby reducing testicular androgen action becomes ineffective. A common mechanism of this transition is intratumoral production of testosterone (T) using the adrenal androgen precursor dehydroepiandrosterone (DHEA) through enzymatic conversion by 3β- and 17β-hydroxysteroid dehydrogenases (3βHSD and 17βHSD). Given the ability of prostate cancer to form blastic metastases in bone, we hypothesized that osteoblasts might be a source of androgen synthesis. RNA expression analyses of murine osteoblasts and human bone confirmed that at least one 3βHSD and 17βHSD enzyme isoform was expressed, suggesting that osteoblasts are capable of generating androgens from adrenal DHEA. Murine osteoblasts were treated with 100 nM and 1 μM DHEA, or vehicle control. Conditioned media from these osteoblasts were assayed for intermediate and active androgens by liquid chromatography-tandem mass spectrometry. As DHEA was consumed, the androgen intermediates androstenediol and androstenedione were generated and subsequently converted to T. Conditioned media of DHEA-treated osteoblasts increased androgen receptor (AR) signaling, PSA production, and cell numbers of the androgen-sensitive prostate cancer cell lines C4-2B and LNCaP. DHEA did not induce AR signaling in osteoblasts despite AR expression in this cell type. We describe an unreported function of osteoblasts as a source of T that is especially relevant during androgen-responsive metastatic prostate cancer invasion into bone.
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影响因子：
5.8
作者：
Banker, Margaret;Puttabyatappa, Muraly;Padmanabhan, Vasantha
通讯作者：
Padmanabhan, Vasantha
影响因子：
6.2
作者：
Chiang, Cherie;Chiu, Maria;Davey, Rachel A.
通讯作者：
Davey, Rachel A.
影响因子：
11.5
作者：
Blaszczyk, N;Masri, BA;Sadar, MD
通讯作者：
Sadar, MD
影响因子：
45.3
作者：
Efstathiou, Eleni;Titus, Mark;Logothetis, Christopher J.
通讯作者：
Logothetis, Christopher J.
DOI：
10.1007/978-1-61779-415-5_2
发表时间：
2012-01-01
期刊：
BONE RESEARCH PROTOCOLS, SECOND EDITION
影响因子：
--
作者：
Bakker, Astrid D.;Klein-Nulend, Jenneke
通讯作者：
Klein-Nulend, Jenneke