Communication and Chemoprevention of Prostate Cancer

前列腺癌的通讯和化学预防

• 批准号: 7045967
• 负责人: Parmender Paul Mehta
• 金额: $ 26.97万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7045967
• 关键词: 1,25 dihydroxycholecalciferol; androgens; athymic mouse; cell adhesion; cell cell interaction; cell line; chemoprevention; gap junctions; membrane channels; molecular assembly /self assembly; neoplastic growth; prostate neoplasms; retinoate

DESCRIPTION (provided by applicant): The role of cell contact-dependent communication in the progression of prostate cancer from a slow-growing hormone (androgen)-dependent state to a highly malignant, hormone-independent state is not fully understood. Cell contact-dependent communication is often mediated by cell adhesion molecules which often get clustered into macromolecular assemblies called cell junctions. Gap junctions, which are formed of proteins called connexins, are a special class of cell junctions that provide a direct cell-cell communication pathway for the passage of signaling molecules between adjoining cells. Our studies have shown that epithelial cells from prostate tumors show diminished, or loss of, connexin expression during prostate cancer progression. Re-expression of connexins in connexin-deficient, androgen-dependent prostate cancer cell line, LNCaP, restores communication and retards growth, whereas that into invasive, androgen-independent cell line, PC-3, results in intracellular connexin accumulation due to impaired trafficking. Intriguingly, treatment of connexin-expressing LNCaP cells with the androgens, which are known to maintain the differentiated state of normal prostate epithelial cells, and facilitate prostate cancer progression, as well as with chemopreventive agents - such as all-trans- and 9-Cis-retinoic acids and 1,25 (OH)2 vitamin D3 either alone or in combination - facilitates the assembly of connexins into gap junctions and their removal degrades gap junctions. We have hypothesized that trafficking of connexins and their assembly into gap junctions are regulated by cellcell adhesion, which becomes defective during the progression of prostate cancer .We have further hypothesized that the physiological modulators of prostate growth and cancer - such as the androgens, alltrans- and 9-Cis-retinoic acids and 1,25 (OH)2 D3 - act as chemopreventive agents by regulating the trafficking of connexins and their assembly and disassembly into gap junctions either directly or indirectly through their effect on cell-cell adhesion. We have proposed 4 specific aims to test these hypotheses. Aim 1 will elucidate the cellular and molecular mechanisms by which androgens and 9-Cis-retinoic acid and 1,25 (OH)2 D3, either alone or in combination, enhance the formation of gap junctions. In aim 2 we will analyze how these agents prevent the degradation of gap junctions in androgen-independent and dependent prostate cancer cell lines. Aim 3 investigates whether androgens and 9-Cis-retinoic acids and 1,25 (OH)2 vitamin D3, enhance the formation of gap junctions between androgen-dependent and androgen-independent prostate cancer cells. Aim 4 will test formation and degradation of gap junctions are regulated by androgens, 9-Cis-retinoic acid and 1,25 (OH)2 vitamin Da in tumors at Ectopic and orthotopic sites in nude mice. Because of the potential interactions among androgens, 9-Cis-retinoic acid and 1,25 (OH)2 vitamin Da receptor pathways, an investigation into their additive and/or synergistic effects on the assembly and disassembly of connexins into gap junctions may shed light on the mechanism by which these agents affect growth, differentiation and apoptosis of normal and prostate cancer cells in vitro and in vivo and act as chemopreventive agents.

描述（由申请人提供）：细胞接触依赖性通讯在前列腺癌从生长缓慢的激素（雄激素）依赖性状态发展为高度恶性、激素非依赖性状态的过程中的作用尚未完全了解。细胞接触依赖性通讯通常由细胞粘附分子介导，细胞粘附分子通常聚集成称为细胞连接的大分子组件。间隙连接由称为连接蛋白的蛋白质形成，是一类特殊的细胞连接，为相邻细胞之间的信号分子通过提供直接的细胞间通讯途径。我们的研究表明，前列腺肿瘤的上皮细胞在前列腺癌进展过程中连接蛋白表达减少或丧失。在连接蛋白缺陷、雄激素依赖性前列腺癌细胞系 LNCaP 中重新表达连接蛋白，可恢复通讯并延缓生长，而在侵入性、雄激素非依赖性细胞系 PC-3 中重新表达连接蛋白，会因运输受损而导致细胞内连接蛋白积累。有趣的是，用雄激素（已知雄激素可维持正常前列腺上皮细胞的分化状态并促进前列腺癌进展）以及化学预防剂（例如全反式和 9-顺式）治疗表达连接蛋白的 LNCaP 细胞-视黄酸和 1,25 (OH)2 维生素 D3 单独或组合使用 - 促进连接蛋白组装成间隙连接，并且它们的去除会降低间隙路口。我们假设连接蛋白的运输及其组装成间隙连接受到细胞粘附的调节，细胞粘附在前列腺癌的进展过程中变得有缺陷。我们进一步假设前列腺生长和癌症的生理调节剂 - 例如雄激素、全反式 -和 9-Cis-视黄酸和 1,25 (OH)2 D3 - 通过调节连接蛋白的运输及其在间隙中的组装和拆卸来充当化学预防剂连接直接或间接通过其对细胞-细胞粘附的影响。我们提出了 4 个具体目标来检验这些假设。目标 1 将阐明雄激素、9-Cis-视黄酸和 1,25 (OH)2 D3（单独或组合）增强间隙连接形成的细胞和分子机制。在目标 2 中，我们将分析这些药物如何防止雄激素非依赖性和依赖性前列腺癌细胞系中间隙连接的降解。目标 3 研究雄激素、9-Cis-视黄酸和 1,25 (OH)2 维生素 D3 是否增强雄激素依赖性和雄激素非依赖性前列腺癌细胞之间间隙连接的形成。目标 4 将测试裸鼠异位和原位肿瘤中雄激素、9-顺式视黄酸和 1,25 (OH)2 维生素 Da 调节间隙连接的形成和降解。由于雄激素、9-Cis-视黄酸和 1,25 (OH)2 维生素 Da 受体途径之间存在潜在的相互作用，因此研究它们对连接蛋白组装和分解为间隙连接的相加和/或协同作用可能会有所启发。研究这些药物在体外和体内影响正常细胞和前列腺癌细胞生长、分化和凋亡的机制，并作为化学预防剂。