Liu Xin-Hua, Kirschenbaum Alexander, Yao Shen, Liu Guizhong, Aaronson Stuart A, Levine Alice C
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Cancer Res. 2007 Jun 15;67(12):5747-53. doi: 10.1158/0008-5472.CAN-07-0478.
The high morbidity and mortality associated with prostate cancer (PCa) result from its tendency to metastasize to bone where it produces predominantly osteoblastic lesions. The Wnt signaling pathway plays an important role in embryogenesis, tumorigenesis, osteoblast development, and bone formation. Androgen signaling via the androgen receptor (AR) is critical in both PCa and bone cell growth. We examined the effects of androgens on cell growth and Wnt signaling in the AR-positive MDA-PCa-2b cell line and MC3T3 preosteoblasts, grown alone and in coculture. We show that the potent androgen dihydrotestosterone increases AR expression and transcriptional activity only in the preosteoblasts. Although dihydrotestosterone induced an 80% increase in PCa cell growth when the cells were grown alone, dihydrotestosterone had a more significant effect on MDA-PCa-2b cell proliferation (3.2-fold increase) when the PCa cells were cocultured with preosteoblasts. Dihydrotestosterone addition to preosteoblasts promoted Wnt-dependent transcriptional reporter activity associated with GSK3beta(S-9) phosphorylation and accumulation of nuclear beta-catenin as well as elevated Runx2 expression. In addition, the increased proliferation of PCa cells in coculture with MC3T3 cells in response to dihydrotestosterone was abrogated by the addition of either exogenous DKK-1 or sFRP-1 protein, two naturally occurring Wnt antagonists. Finally, we show that the paracrine growth-promoting effect of androgens is limited to MDA-PCa-2b cells. These data imply that Wnt signaling is involved in the androgen-regulated crosstalk between preosteoblasts and PCa cells and suggest that androgens may stimulate growth of some prostate tumor cells indirectly, via up-regulation of Wnt signaling in bone cells.
前列腺癌（PCa）的高发病率和死亡率源于其易于转移至骨骼并在那里产生主要为成骨细胞性病变的倾向。Wnt信号通路在胚胎发育、肿瘤发生、成骨细胞发育和骨形成中发挥重要作用。经由雄激素受体（AR）的雄激素信号传导在PCa和骨细胞生长中均至关重要。我们研究了雄激素对单独培养和共培养的AR阳性MDA-PCa-2b细胞系和MC3T3前成骨细胞的细胞生长和Wnt信号传导的影响。我们发现强效雄激素双氢睾酮仅在前成骨细胞中增加AR表达和转录活性。虽然双氢睾酮在单独培养PCa细胞时可使细胞生长增加80%，但当PCa细胞与前成骨细胞共培养时，双氢睾酮对MDA-PCa-2b细胞增殖的影响更为显著（增加3.2倍）。将双氢睾酮添加到前成骨细胞中可促进与GSK3β（S-9）磷酸化、核β-连环蛋白积累以及Runx2表达升高相关的Wnt依赖性转录报告活性。此外，添加两种天然存在的Wnt拮抗剂外源性DKK-1或sFRP-1蛋白可消除双氢睾酮刺激下PCa细胞与MC3T3细胞共培养时增殖的增加。最后，我们表明雄激素的旁分泌生长促进作用仅限于MDA-PCa-2b细胞。这些数据表明Wnt信号传导参与了前成骨细胞与PCa细胞之间雄激素调节的相互作用，并提示雄激素可能通过上调骨细胞中的Wnt信号传导间接刺激某些前列腺肿瘤细胞的生长。
