Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells
Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells
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DOI：
10.1158/1078-0432.ccr-0974-3
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发表时间：
2004-03-01
影响因子：
11.5
通讯作者：
Sadar, MD
中科院分区：
文献类型：
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作者：
Blaszczyk, N;Masri, BA;Sadar, MD
目的：前列腺癌转移至骨骼形成成骨细胞病变。雄激素消融术是目前转移性前列腺癌的治疗方法。这种治疗是治标不治本的，并且这种疾病会以雄激素不依赖的形式复发，在此之前，前列腺特异性抗原（PSA）的滴度会上升。在这里，我们研究了人类成骨细胞可能分泌导致雄激素非依赖型前列腺癌出现的因子的可能性。实验设计：将人成骨细胞原代培养物作为条件培养基（OCM）的来源。利用3-（4,5-二甲基噻唑-2-酰基）-2,5-二苯基溴化四唑（MTT）检测、Northern blot分析和报告基因构建，监测LNCaP人前列腺癌细胞对OCM的增殖、雄激素调节基因的表达和雄激素受体（AR）的反激活。测量OCM中存在的白细胞介素-6 （IL-6）水平，并通过抗IL-6抗体中和研究其对PSA增殖和表达的贡献。结果：OCM使LNCaP细胞中PSA蛋白和RNA水平的增殖和表达增加。在OCM和雄激素共同处理的细胞中，检测到PSA (6.1 kb)-和pARR(3)-tk-荧光素酶报告蛋白活性的协同增加。OCM靶向AR的nh2末端结构域，OCM对AR转录活性的影响被一种抗雄激素抑制。IL-6中和抗体阻断OCM对PSA的增殖和表达。结论：成骨细胞分泌IL-6等因子，通过部分依赖于AR的机制诱导雄激素不依赖型PSA基因的表达和前列腺癌细胞的增殖，明确这种分子机制可能有助于改善转移性前列腺癌的临床管理。
Purpose: Prostate cancer metastasizes to the skeleton to form osteoblastic lesions. Androgen ablation is the current treatment for metastatic prostate cancer. This therapy is palliative, and the disease will return in an androgen-independent form that is preceded by a rising titer of prostate-specific antigen (PSA). Here, we investigated the possibility that human osteoblasts might secrete factors that contribute to the emergence of androgen-independent prostate cancer.Experimental Design: Primary cultures of human osteoblasts were used as a source of conditioned medium (OCM). Proliferation, expression of androgen-regulated genes, and transactivation of the androgen receptor (AR) were monitored in LNCaP human prostate cancer cells in response to OCM using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Northern blot analysis, and reporter gene constructs. Levels of interleukin-6 (IL-6) present in OCM were measured, and its contribution to proliferation and expression of PSA were investigated by neutralization studies with anti IL-6 antibodies.Results: OCM increased the proliferation and expression of PSA at both the protein and RNA levels in LNCaP cells. Synergistic increases in the activities of PSA (6.1 kb)- and pARR(3)-tk-luciferase reporters were measured in cells cotreated with both OCM and androgen. OCM targeted the NH2-terminal domain of the AR. The effect of OCM on transcriptional activity of the AR was inhibited by an antiandrogen. Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM.Conclusion: Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the AR. Identifying such molecular mechanisms may lead to improved clinical management of metastatic prostate cancer.