PROSTAGLANDIN E2 PROMOTES TUMOR DISSEMINATION

前列腺素 E2 促进肿瘤播散

• 批准号: 2091725
• 负责人: M. Rita Young
• 金额: $ 9.9万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2091725
• 关键词: cell migration; clone cells; cyclic AMP; enzyme activity; host neoplasm interaction; laboratory mouse; lung neoplasms; metastasis; neoplasm /cancer invasiveness; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; neoplastic cell; phosphoprotein phosphatase; phosphorylation; prostaglandin E; prostaglandin inhibitors; protein kinase A; tumor promoters

During the currently funded study, prostaglandin E2 (PGE2) was shown to stimulate invasion and metastasis by metastatic Lewis lung carcinoma (LLC) clones. This appeared to be dependent on generation of a cAMP response and, in turn, activation of protein kinase A (PKA). In nonmetastatic LLC, PGE2 elevated cAMP levels, but this did not significantly activate PKA or stimulate metastatic properties, even though their PKA could be activated extracellularly. These data suggest that PKA activity and PKA-stimulated metastasis may be more tightly regulated in nonmetastatic LLC than in metastatic LLC. Further studies implicated dephosphorylation reactions of protein phosphatases (PP) -1 and -2A as the regulatory controls for PKA in nonmetastatic LLC. The hypothesis of this study is that in metastatic LLC, defective regulation of PKA activity by PP-1/2A leads to a heightened PKA response to PGE2 and, in turn, stimulation of metastasis. Studies to assess the role of PKA activation in stimulation of metastasis will be accomplished with the use of wild-type metastatic and nonmetastatic LLC, LLC transfectants that either overexpress the Calpha subunit of PKA or express a mutant RIalpha that blocks PKA activation, and by modulating the level of expression of these subunits with Zn2+. The first objective of this study will identify if and how PKA activation in LLC variants leads to increased metastasis from a s.c. or orthotopically implanted tumor site. The second objective will identify points at which metastatic and nonmetastatis LLC might diverge in the PKA activation process. The third objective will determine if the balance between phosphorylation by PKA and dephosphorylation by PP-1/2A regulates the metastatic properties of LLC. These studies will result in an understanding of intracellular mechanisms which regulate PKA activity and how defects in these regulatory controls increase metastasis. Future studies will then be planned to develop strategies by which to stimulate PP-1/2A so as to block PKA stimulation of metastasis.

在目前资助的研究中，前列腺素 E2 (PGE2) 被证明可以 刺激转移性Lewis肺癌（LLC）的侵袭和转移 克隆。 这似乎取决于 cAMP 反应的产生 进而激活蛋白激酶 A (PKA)。 在非转移性 LLC 中， PGE2 升高了 cAMP 水平，但这并没有显着激活 PKA 或 刺激转移特性，即使它们的 PKA 可以被激活 细胞外。 这些数据表明 PKA 活性和 PKA 刺激 非转移性 LLC 中的转移可能比非转移性 LLC 中受到更严格的监管 转移性有限责任公司。 进一步的研究表明去磷酸化反应 蛋白磷酸酶 (PP) -1 和 -2A 作为 PKA 的调节控制 非转移性有限责任公司。 本研究的假设是，在转移性 LLC 中，缺陷 PP-1/2A 对 PKA 活性的调节导致 PKA 反应增强 PGE2 进而刺激转移。 评估作用的研究 PKA 激活在刺激转移中的作用将通过 使用野生型转移性和非转移性 LLC、LLC 转染子 过度表达 PKA 的 Calpha 亚基或表达突变体 RIalpha 阻断 PKA 激活，并通过调节 这些亚基与 Zn2+ 的表达。 本研究的第一个目标是确定 PKA 是否激活以及如何激活 LLC 变体会导致皮下转移增加。或原位地 植入肿瘤的部位。 第二个目标将确定以下几点： 转移性和非转移性 LLC 在 PKA 激活方面可能存在差异 过程。 第三个目标将决定两者之间是否达到平衡 PKA 磷酸化和 PP-1/2A 去磷酸化调节 LLC的转移特性。 这些研究将有助于了解细胞内机制 调节 PKA 活性以及这些调节控制中的缺陷如何 增加转移。 未来的研究将计划发展 刺激 PP-1/2A 从而阻断 PKA 刺激的策略 转移。