Prostate cancer prevention by selenium supplementation

补硒预防前列腺癌

• 批准号: 7736130
• 负责人: RAYUDU GOPALAKRISHNA
• 金额: $ 33.82万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736130
• 关键词: Acids; Affect; Americas; Binding; Biological Models; Carcinogens; Cell Death; Cell Death Inhibition; Cell Survival; Cells; Chemoprevention; Effectiveness; Epithelial Cells; Exposure to; Figs - dietary; Generations; Genetic; Human; Induction of Apoptosis; Intraepithelial Neoplasia; Isoenzymes; LIM Domain; Lipid Peroxides; Malignant Neoplasms; Malignant neoplasm of prostate; Micronutrients; Minor; Modeling; Modification; Normal Cell; Normal tissue morphology; Nude Mice; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Peroxides; Premalignant; Preventive; Prostate; Prostatic Neoplasms; Protein Kinase C; Research Design; Resistance; Resistance development; Role; Safety; Selenium; Signal Induction; Signal Transduction; Staging; Supplementation; System; Testing; Thioredoxin; Tissues; Toxic effect; Tumor Promoters; Tumor Promotion; Work; Zinc Fingers; base; cancer cell; cancer diagnosis; carbene; carcinogenesis; citrate carrier; cytotoxic; cytotoxicity; dietary supplements; feeding; methylselenic acid; neoplastic cell; oxidation; prevent; prostate cancer prevention; prostate carcinogenesis; public health relevance; restoration; selenocyanate; selenol; selenomethylselenocysteine; selenoprotein; thioredoxin reductase; tumor; tumor progression

DESCRIPTION (provided by applicant): Selenium prevents cancer in some cases and fails to prevent it in other cases. Furthermore, in some cases, it may cause toxicity to the host. Therefore, there is a need to understand its cancer preventive mechanism in order to optimize its effectiveness. The following hypothesis will be tested: Redox-active selenometabolites exert their cancer-preventive actions, at least in part, through oxidation of unique cysteine- rich regions and zinc fingers present in protein kinase C (PKC), a known target for a variety of tumor promoters. Importantly, PKC oxidation induced by selenometabolites can be reversed by another product of selenium, the selenoprotein thioredoxin reductase (TR). In preneoplastic prostate cells, a low amount of methylselenol, a volatile selenometabolite, reacts with tumor-promoting peroxides and is converted into seleninic acid, which is better retained and amplified through redox cycling. Seleninic acid inactivates PKC resulting in inhibition of tumor promotion and induction of apoptosis. Normal tissues generally are protected from selenometabolites by TR, whose action is compromised in precancer cells. Advanced tumor cells escape the cancer-preventive actions of selenium via the increased expression of PKC isoenzymes (Se- sensitive 1or Se-resistant 5) and selenoprotein (TR) which naturally occurs in tumor progression. Major emphasis is placed on evaluating the selective cytotoxicity of low tissue-available concentrations (nM) of selenium to promoting precancer cells and distinguishing it from the nonselective global toxicity seen at higher concentrations (5M). Initially, we will use a prostate carcinogenesis model employing carcinogen-initiated human prostate epithelial cells (RWPE-1) grown in culture. The results obtained will then be further validated by extending this model to nude mice fed a diet supplemented with Se-methylselenocysteine or 1,4- phenylene-bis(methylene)selenocyanate. Next, we will use various prostate tumor cells representing early (prostate intraepithelial neoplasia) and advanced stages of malignancy derived from a single clone of RWPE-1 cells to determine the mechanistic basis for the differences in cellular sensitivity to selenium at various stages of prostate cancer. The first aim is to evaluate the causal role of selenium-induced inactivation of PKC1 in the inhibition of tumor promotion in prostate precancer cells. We will also assess the mechanism by which the protective function of selenoprotein (TR) is compromised in precancer cells, allowing the selective toxicity of selenium to occur. The second aim is to assess the significance of selenol action, as amplified by redox cycling with tumor-promoting peroxides, in redirecting tumor promoter-induced signaling from induction of cell survival to "restoration" of cell death. The final aim is to evaluate how the proposed mechanism that is cytotoxic to precancer cells results in safety to normal cells and development of resistance in advanced prostate cancer cells. These mechanistic studies will help us to understand why in some cases selenium successfully prevents cancer, while in other cases it fails and even can cause toxicity to the host. PUBLIC HEALTH RELEVANCE: Micronutrient selenium is a promising cancer-preventive agent. Some cases it works and in other cases it fails to prevent cancer. Understanding the mechanisms by which it prevents cancer or causes toxicity will allow us to optimize its use as a safe cancer-preventive agent.

描述（由申请人提供）：硒在某些情况下可以防止癌症，在其他情况下无法阻止癌症。此外，在某些情况下，可能会对宿主引起毒性。因此，为了优化其有效性，需要了解其癌症预防机制。将检验以下假设：氧化还原活性硒代谢物至少部分通过氧化为蛋白激酶C（PKC）中的独特的富含半胱氨酸的区域和锌指的氧化，这是一种已知的蛋白激酶C（PKC），这是多种肿瘤启动子的已知靶标。重要的是，硒代谢物诱导的PKC氧化可以被硒的另一种产品，硒蛋白硫氧还蛋白还原酶（TR）逆转。在癌性前列腺细胞中，低量的甲基塞列诺（一种挥发性硒代谢物）与促肿瘤的过氧化物反应，并转化为硒酸，通过氧化还原循环更好地保留并扩增。硒酸使PKC失活，从而抑制肿瘤促进和诱导凋亡。正常组织通常通过TR保护硒代谢物，其作用在预科细胞中受到损害。晚期肿瘤细胞通过增加PKC同工酶（Sementive 1或Se-Se耐药5）和硒蛋白（TR）的表达来逃脱硒的癌症预防作用。重点放在评估硒低组织可用浓度（NM）的选择性细胞毒性上，以促进前癌细胞，并将其与在较高浓度（5M）下的非选择性全局毒性区分开。最初，我们将使用采用培养中种植的致癌人前列腺上皮细胞（RWPE-1）的前列腺致癌模型。然后，通过将该模型扩展到补充了含有se-甲基塞林诺半胱氨酸或1,4-苯基双（亚甲基）硒烯酸的饮食的裸小鼠，将获得的结果进一步验证。接下来，我们将使用代表早期（前列腺上皮内肿瘤）的各种前列腺肿瘤细胞和源自RWPE-1细胞单个克隆的恶性肿瘤的晚期阶段，以确定在前列腺癌的各个阶段对硒敏感性差异的机械基础。第一个目的是评估硒诱导的PKC1灭活在抑制前列腺癌细胞抑制肿瘤促进细胞中的因果作用。我们还将评估硒蛋白（TR）的保护功能在预科细胞中损害的机制，从而使硒的选择性毒性发生。第二个目的是评估硒醇作用的显着性，这是通过用肿瘤促进过氧化物循环的氧化还原循环的放大，这在重定向肿瘤启动子诱导的信号传导中，从诱导细胞存活到细胞死亡的“恢复”。最终目的是评估针对前疗细胞的细胞毒性机制如何使正常细胞的安全性和晚期前列腺癌细胞中的耐药性发展。这些机械研究将有助于我们了解为什么在某些情况下，硒可以成功防止癌症，而在其他情况下，它会失败，甚至可能对宿主引起毒性。公共卫生相关性：微量营养素硒是一种有前途的预防剂。在某些情况下，它有效，在其他情况下，它无法预防癌症。了解防止癌症或引起毒性的机制将使我们能够优化其作为安全癌症预防剂的使用。