SIGNAL TRANSDUCTION EVENTS AND THE REGULATION OF CELL GROWTH

这个项目是为了增加我们对生物的了解 前列腺癌和开发治疗前列腺癌的新方法 晚期前列腺癌的信号转导研究 调节人前列腺癌细胞系生长的事件。 这项工作目前集中在(1)cAMP对生长和 分化，以及(2)通过激活P2- 嘌呤能受体。我们发现细胞内cAMP的升高是 对所有测试的前列腺癌细胞株都有高度的生长抑制作用， 并在四个细胞系中的两个诱导神经元形态。所有的 细胞株表达一个或多个神经内分泌标志物 分化，包括致密核心颗粒、NSE、S100和 神经丝蛋白。与分子肿瘤学合作 组，CPB，我们检测了该基因的表达和活性 神经内分泌标志物pp60c-src并发现高水平的src激酶 CAMP处理后活性升高。在协作中 在CPB的肿瘤细胞生物科，我们发现两种阿萨霉素 据报道，抑制src活性的抗生素效力很强。 所有前列腺癌细胞系中的细胞毒剂。对中国传统文化的研究 CAMP诱导生长抑制的机制证明cAMP 诱导分泌具有生物活性的转化生长因子-β2，增加转化生长因子-β2 CAMP反应元件在转化生长因子-β2中的转录和激活 推动者。P2-嘌呤能受体研究表明 雄激素非依赖性前列腺癌细胞株表达P2-嘌呤能 与磷脂酶C激活、急性钙离子偶联的受体 动员，诱导长时间的钙振荡，生长 逮捕和细胞死亡。在雄激素敏感细胞系LNCaP中， 然而，P2激动剂不能刺激磷脂酶C活性，不能 诱导钙离子释放，且不抑制生长，而两种细胞类型 表达了特定的P2受体，具有可比性的KD和Bmax，这些数据 强烈影响磷脂酶C的激活和钙离子的延长 动员在细胞生长抑制和细胞毒作用中的作用 P2-嘌呤能受体激动剂。

This project is designed to increase our understanding of the biology of prostate cancer and to develop a new approach to the treatment of advanced prostatic cancer through the study of the signal transduction events regulating the growth of human prostate carcinoma cell lines. This work is currently focused on (1) effects of cAMP on growth and differentiation, and (2) cytotoxicity through activation of P2- purinergic receptors. We found that elevation of intracellular cAMP is highly growth-inhibitory to all prostate carcinoma cell lines tested, and induces neuronal morphology in two of four cell lines. All of the cell lines expressed one or more markers of neuroendocrine differentiation, including dense core granules, NSE, S100, and neurofilament proteins. In collaboration with the Molecular Oncology Group, CPB, we tested for the expression and activity of the neuroendocrine marker pp60c-src and found high levels of src kinase activity that were increased after cAMP treatment. In collaboration with the Tumor Cell Biology Section, CPB, we found that two ansamycin antibiotics reported to inhibit src activity were highly potent cytotoxic agents in all prostatic carcinoma cell lines. Studies of the mechanism of cAMP-induced growth inhibition demonstrated that cAMP induces the secretion of bioactive TGF-Beta2, an increase in TGF-Beta2 transcription, and activation of cAMP response elements in the TGF-Beta2 promoter. P2-purinergic receptor studies demonstrated that androgen-independent prostate carcinoma cell lines express P2-purinergic receptors that are coupled to phospholipase C activation, acute Ca+ mobilization, the induction of prolonged Ca2+ oscillations, growth arrest, and cell death. In the androgen-sensitive cell line LNCaP, however, P2 agonists did not stimulate phospholipase C activity, did not induce Ca2+ release, and did not inhibit growth, while both cell types expressed specific P2 receptors, with comparable Kd and Bmax, These data strongly implicate phospholipase C activation and prolonged Ca2+ mobilization in the growth-inhibitory and cytotoxic effect of P2-purinergic receptor agonists.