SIGNAL TRANSDUCTION EVENTS AND THE REGULATION OF CELL GROWTH

信号转导事件和细胞生长的调节

• 批准号: 3853226
• 负责人: J B TREPEL
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3853226
• 关键词: DiGeorge's syndrome; androgen receptor; antineoplastic antibiotics; biological signal transduction; biomarker; calcium flux; cell differentiation; cell growth regulation; clone cells; gene expression; hormone related neoplasm /cancer; human tissue; neoplastic cell; neoplastic growth; neuroendocrine system; phospholipase C; prostate neoplasms; purine /pyrimidine metabolism; receptor coupling; transforming growth factors

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.

这个项目旨在增加我们对生物学的理解， 前列腺癌，并开发一种新的方法来治疗 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对生长的影响， 分化，和（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系高度生长抑制， 并在四种细胞系中的两种中诱导神经元形态。 所有 细胞系表达一种或多种神经内分泌标志物 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，我们检测了表达和活性的 神经内分泌标志物pp60c-src，发现src激酶水平高 cAMP处理后活性增加。 合作 与肿瘤细胞生物学科，CPB，我们发现，两个安莎霉素， 据报道，抑制src活性的抗生素非常有效， 在所有前列腺癌细胞系中的细胞毒性剂。 的研究 cAMP诱导的生长抑制机制表明，cAMP 诱导生物活性TGF-β 2的分泌， TGF-β 2中cAMP反应元件的转录和激活 启动子 P2-嘌呤能受体研究表明， 雄激素非依赖性前列腺癌细胞系表达P2-嘌呤能 与磷脂酶C激活偶联的受体，急性Ca + 动员，诱导长时间的Ca2+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激动剂不刺激磷脂酶C活性， 诱导Ca2+释放，且不抑制生长，而两种细胞类型 表达特异性P2受体，具有可比的Kd和Bmax，这些数据 强烈暗示磷脂酶C激活和延长的Ca 2 + 动员的生长抑制和细胞毒性作用 P2-嘌呤能受体激动剂。