Prostate cancer prevention by selenium supplementation

说明(申请人提供)：硒在某些情况下可以预防癌症，但在其他情况下不能预防癌症。此外，在某些情况下，它可能会对宿主造成毒性。因此，有必要了解其防癌机制，以优化其疗效。以下假设将得到验证：氧化还原活性的硒代谢产物至少部分通过氧化蛋白激酶C(PKC)中独特的半胱氨酸富集区和锌指发挥其预防癌症的作用，PKC是各种肿瘤促进剂的已知靶标。重要的是，硒代谢诱导的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，一种挥发性的硒代谢产物，与促进肿瘤的过氧化物反应，转化为亚硒酸，通过氧化还原循环更好地保留和放大。亚硒酸使PKC失活，从而抑制肿瘤的发生和诱导细胞凋亡。正常组织通常受到TRR的保护，使其免受硒代谢的影响，其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(硒敏感的1或抗硒的5)和硒蛋白(Tr)的表达来逃避硒的防癌作用，后者自然地出现在肿瘤进展中。主要重点是评估低组织有效浓度(NM)的硒对促进癌前细胞的选择性细胞毒性，并将其与较高浓度(5M)的非选择性全局毒性区分开来。首先，我们将使用前列腺癌模型，使用在培养中生长的致癌物质启动的人前列腺上皮细胞(RWPE-1)。然后，通过将该模型扩展到裸鼠，以补充硒-甲基半胱氨酸或1，4-苯亚甲基双(亚甲基)硒氰酸盐的饲料，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，以确定前列腺癌不同阶段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的PKC1失活在抑制前列腺癌前细胞促癌作用中的因果作用。我们还将评估硒蛋白(TR)的保护功能在癌前细胞中受到损害的机制，从而允许硒的选择性毒性发生。第二个目的是评估硒的作用，如通过氧化还原循环与促肿瘤的过氧化物化放大，在将肿瘤启动子诱导的信号从诱导细胞存活重定向到细胞死亡的“恢复”中的意义。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导致对正常细胞的安全性和晚期前列腺癌细胞的耐药性发展。这些机理研究将帮助我们理解为什么在某些情况下，硒可以成功地预防癌症，而在另一些情况下，它却失败了，甚至会对宿主造成毒性。与公共健康相关：微量营养素硒是一种很有前途的防癌药物。在某些情况下，它是有效的，在另一些情况下，它无法预防癌症。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防御剂的使用。

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.