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Prostate cancer prevention by selenium supplementation

补硒预防前列腺癌

基本信息

批准号：
8267106
负责人：
RAYUDU GOPALAKRISHNA
金额：
$ 32.61万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267106
关键词：
Acids Affect Americas Binding Biological Models Carcinogens Cell Death Cell Death Inhibition Cell Survival Cells Chemoprevention Effectiveness Epithelial Cells Exposure to Generations Genetic Health 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 cytotoxic cytotoxicity dietary supplements feeding methylselenic acid neoplastic cell oxidation prevent prostate cancer prevention prostate carcinogenesis restoration selenocyanate selenol selenomethylselenocysteine selenoprotein thioredoxin reductase tumor tumor progression

项目摘要

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预防癌症，在其他情况下不能预防癌症。此外，在某些情况下，它可能对宿主造成毒性。因此，有必要了解其防癌机制，以优化其有效性。以下假设将被验证：氧化还原活性硒代谢物发挥其预防癌症的作用，至少部分是通过氧化蛋白激酶C （PKC）中独特的富含半胱氨酸的区域和锌指，PKC是多种肿瘤启动子的已知靶点。重要的是，硒代谢物诱导的PKC氧化可以被硒的另一种产物硒蛋白硫氧还蛋白还原酶（TR）逆转。在癌前前列腺细胞中，少量的甲基硒醇（一种挥发性硒代谢物）与促进肿瘤的过氧化物发生反应，转化为亚硒酸，亚硒酸通过氧化还原循环得到更好的保留和放大。硒酸使PKC失活，抑制肿瘤促进和诱导细胞凋亡。正常组织通常受到TR的保护，免受硒代谢物的影响，而TR的作用在癌前细胞中受到损害。晚期肿瘤细胞通过增加PKC同工酶（硒敏感1或硒抗性5）和硒蛋白（TR）的表达来逃避硒的癌症预防作用，这在肿瘤进展中自然发生。主要重点是评估低组织有效浓度（nM）硒对促进癌前细胞的选择性细胞毒性，并将其与高浓度（5M）的非选择性整体毒性区分开来。首先，我们将使用一种前列腺癌变模型，使用在培养中生长的致癌物质引发的人类前列腺上皮细胞（RWPE-1）。通过将该模型扩展到饲喂添加硒-甲基硒半胱氨酸或1,4-苯-二（亚甲基）硒氰酸盐的裸鼠，将进一步验证所获得的结果。接下来，我们将使用来自单个RWPE-1细胞克隆的代表早期（前列腺上皮内瘤变）和晚期恶性肿瘤的各种前列腺肿瘤细胞来确定不同阶段前列腺癌细胞对硒敏感性差异的机制基础。第一个目的是评估硒诱导PKC1失活在抑制前列腺癌前细胞肿瘤促进中的因果作用。我们还将评估硒蛋白（TR）的保护功能在癌前细胞中受损的机制，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重要性，通过与促肿瘤过氧化物的氧化还原循环放大，将肿瘤启动子诱导的信号从诱导细胞存活转向“恢复”细胞死亡。最终目的是评估所提出的对癌前细胞具有细胞毒性的机制如何对正常细胞产生安全性以及在晚期前列腺癌细胞中产生耐药性。这些机制研究将帮助我们理解为什么在某些情况下硒成功地预防癌症，而在其他情况下它失败，甚至可能对宿主造成毒性。公共卫生相关性：微量营养素硒是一种很有前途的癌症预防剂。在某些情况下，它有效，而在其他情况下，它不能预防癌症。了解它预防癌症或引起毒性的机制将使我们能够优化其作为安全的癌症预防剂的使用。