van der Deen Margaretha, Akech Jacqueline, Wang Tao, FitzGerald Thomas J, Altieri Dario C, Languino Lucia R, Lian Jane B, van Wijnen Andre J, Stein Janet L, Stein Gary S
Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
J Cell Biochem. 2010 Mar 1;109(4):828-37. doi: 10.1002/jcb.22463.
Prostate cancer cells often metastasize to bone where osteolytic lesions are formed. Runx2 is an essential transcription factor for bone formation and suppresses cell growth in normal osteoblasts but may function as an oncogenic factor in solid tumors (e.g., breast, prostate). Here, we addressed whether Runx2 is linked to steroid hormone and growth factor signaling, which controls prostate cancer cell growth. Protein expression profiling of prostate cell lines (i.e., PC3, LNCaP, RWPE) treated with 5alpha-dihydrotestosterone (DHT) or tumor growth factor beta (TGFbeta) revealed modulations in selected cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors that are generally consistent with mitogenic responses. Endogenous elevation of Runx2 and diminished p57 protein levels in PC3 cells are associated with faster proliferation in vitro and development of larger tumors upon xenografting these cells in bone in vivo. To examine whether TGFbeta or DHT signaling modulates the transcriptional activity of Runx2 and vice versa, we performed luciferase reporter assays. In PC3 cells that express TGFbetaRII, TGFbeta and Runx2 synergize to increase transcription of synthetic promoters. In LNCaP cells that are DHT responsive, Runx2 stimulates the androgen receptor (AR) responsive expression of the prostate-specific marker PSA, perhaps facilitated by formation of a complex with AR. Our data suggest that Runx2 is mechanistically linked to TGFbeta and androgen responsive pathways that support prostate cancer cell growth.
前列腺癌细胞常常转移至骨骼并在那里形成溶骨性病变。Runx2是骨形成所必需的转录因子，在正常成骨细胞中抑制细胞生长，但在实体瘤（如乳腺癌、前列腺癌）中可能作为致癌因子发挥作用。在此，我们探讨了Runx2是否与控制前列腺癌细胞生长的类固醇激素和生长因子信号传导相关。用5α-二氢睾酮（DHT）或肿瘤生长因子β（TGFβ）处理前列腺细胞系（即PC3、LNCaP、RWPE）后的蛋白质表达谱分析显示，所选细胞周期蛋白、细胞周期蛋白依赖性激酶（CDK）和CDK抑制剂发生了变化，这些变化总体上与促有丝分裂反应一致。PC3细胞中Runx2的内源性升高和p57蛋白水平的降低与体外更快的增殖以及将这些细胞移植到体内骨骼后更大肿瘤的形成有关。为了研究TGFβ或DHT信号传导是否调节Runx2的转录活性，反之亦然，我们进行了荧光素酶报告基因检测。在表达TGFβRII的PC3细胞中，TGFβ和Runx2协同作用以增加合成启动子的转录。在对DHT有反应的LNCaP细胞中，Runx2刺激前列腺特异性标志物PSA的雄激素受体（AR）反应性表达，这可能是通过与AR形成复合物来促进的。我们的数据表明，Runx2在机制上与支持前列腺癌细胞生长的TGFβ和雄激素反应途径相关。
