GAP JUNCTIONS AND CELL INTERACTIONS IN PROSTATE CANCER

前列腺癌中的间隙连接和细胞相互作用

• 批准号: 6411185
• 负责人: Parmender Paul Mehta
• 金额: $ 19.42万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6411185
• 关键词: androgens; apoptosis; athymic mouse; biological signal transduction; cadherins; cell cell interaction; cell differentiation; cell growth regulation; epidermal growth factor; extracellular matrix; gap junctions; gene expression; growth factor; hormone regulation /control mechanism; immunocytochemistry; matrigel; membrane channels; molecular assembly /self assembly; neoplastic process; phosphorylation; prostate neoplasms; tissue /cell culture; western blottings

The cell-cell channels in gap junctions, formed of proteins called connexins (Cxs), link the cytoplasmic interiors of adjoining cells and provide an intercellular pathway for the diffusion of growth-regulatory molecules. We have observed alterations in the expression and function of Cx genes between prostate carcinoma and normal prostate cells in vitro. We plan now to delineate these differences and test the hypothesis that a homeostatic mechanism mediated by gap-junctional communication controls the growth, differentiation, and apoptotic death of prostatic epithelial cells and may have a role in preventing the progression of prostate cancer from latency to clinical manifestation. In the first aim, we will explore the cellular and physiological mechanisms by which formation of gap junctions in malignant prostate epithelial cells inhibits growth and induces differentiation and apoptosis through delineation of effects resulting from the diffusion of putative growth- regulatory molecules and the cooperation/redundancy among various kinds of cell junctions, specifically those mediated by E- cadherin. This will be tested by inducing the formation of gap junctions composed of normal Cxs that will allow the passage of putative growth-regulatory molecules and those of mutant Cxs that will impede their passage. In the second aim, we hypothesize that the expression of Cxs and their assembly into gap junctions are regulated by the modulators of prostatic growth and cancer, such as growth factors and the androgens. This hypothesis will be tested by studying the effects of growth factors, known to be produced during the progression of prostate cancer, on the assembly and function of gap junctions composed of Cx32 and Cx43. In the third aim, we hypothesize that signal transduction through cell-matrix adhesion controls the assembly of Cxs into gap junctions, or vice versa, and thereby governs the growth, differentiation, and apoptosis in human prostate cancer cells. This hypothesis will be tested by inducing the formation of gap junctions in human prostate cancer cells, which express Cxs but fail to form gap junctions, by plating them on various components of extracellular matrix and studying the effects on growth, differentiation, and apoptosis. Such experiments should enhance our knowledge about the pathobiology of prostate cancer.

间隙连接中的细胞-细胞通道由称为连接蛋白 (Cxs) 的蛋白质形成，连接相邻细胞的细胞质内部，并为生长调节分子的扩散提供细胞间途径。 我们在体外观察到前列腺癌和正常前列腺细胞之间 Cx 基因表达和功能的变化。 我们现在计划描述这些差异并测试以下假设：间隙连接通讯介导的稳态机制控制前列腺上皮细胞的生长、分化和凋亡，并且可能在阻止前列腺癌从潜伏期进展到临床期方面发挥作用。表现。 在第一个目标中，我们将通过描述假定的生长调节分子的扩散和协作/冗余所产生的效应，探索恶性前列腺上皮细胞中间隙连接的形成抑制生长并诱导分化和凋亡的细胞和生理机制。各种细胞连接之间的连接，特别是由 E-钙粘蛋白介导的细胞连接。 这将通过诱导由正常 Cxs 组成的间隙连接的形成来测试，该间隙连接将允许假定的生长调节分子通过，而突变的 Cxs 将阻碍其通过。 在第二个目标中，我们假设 Cxs 的表达及其组装成间隙连接受到前列腺生长和癌症的调节剂（例如生长因子和雄激素）的调节。 这一假设将通过研究生长因子（已知在前列腺癌进展过程中产生）对由 Cx32 和 Cx43 组成的间隙连接的组装和功能的影响来检验。在第三个目标中，我们假设通过细胞基质粘附的信号转导控制 Cxs 组装成间隙连接，反之亦然，从而控制人前列腺癌细胞的生长、分化和凋亡。这一假设将通过诱导人类前列腺癌细胞中间隙连接的形成来测试，这些细胞表达Cxs但不能形成间隙连接，将它们铺在细胞外基质的各种成分上并研究其对生长、分化和凋亡的影响。 这些实验应该可以增强我们对前列腺癌病理学的了解。