Prevention of PTEN deletion driven prostate cancer by selenium

硒预防 PTEN 缺失导致的前列腺癌

• 批准号: 8028115
• 负责人: YIBIN DENG
• 金额: $ 19.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028115
• 关键词: AKT Signaling Pathway; Adenocarcinoma; Age; Aging; American; Animal Model; Atypical hyperplasia; Automobile Driving; Biochemical; Cancer Burden; Cancer Etiology; Cancer Model; Cancer Patient; Cancerous; Cell Culture Techniques; Cell Death; Cell Proliferation; Cessation of life; Chemicals; Chemoprevention; Chromosomes, Human, Pair 10; Clinical; DU145; Data; Development; Disease Progression; Dose; Epithelial; Etiology; Failure; Future; Generations; Growth; Health Benefit; Histopathology; Human; Immunohistochemistry; Kinetics; Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Metabolic; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; National Cancer Institute; Nature; Neoplasm Metastasis; Neurosecretory Systems; Nude Mice; Oral; Oral Administration; PTEN gene; Pathway interactions; Perception; Phosphorylation; Physiological; Plant Roots; Pre-Clinical Model; Premalignant; Prevention; Preventive; Prostate; Prostate Adenocarcinoma; Prostatic Intraepithelial Neoplasias; Proto-Oncogene Proteins c-akt; Research; Rodent Model; Schedule; Scientist; Selenium; Selenium Compounds; Selenium and Vitamin E Efficacy Trial; Selenomethionine; Signal Pathway; Solid; Staging; Supplementation; Surveys; Techniques; Testing; Tissue Sample; Tissues; Transgenic Organisms; Validation; Weight; Western Blotting; Work; Xenograft Model; Xenograft procedure; cancer diagnosis; cancer initiation; cancer prevention; cancer therapy; carcinogenesis; clinically relevant; clinically significant; cohort; cost effective; diabetes risk; dietary supplements; dosage; human data; human disease; in vivo; indexing; male; men; methylselenic acid; mortality; mouse model; pre-clinical; prevent; prostate cancer prevention; prostate carcinogenesis; research study; response; selenomethylselenocysteine; translational study; tumor progression

DESCRIPTION (provided by applicant): Chemoprevention of prostate carcinogenesis is a plausible and necessary approach to deal with the prostate cancer (PCa) problem at the root. Previous studies have suggested that supplementation of selenium (Se) may prevent or delay human PCa. However, the NCI stopped the Selenium and vitamin E Cancer prevention Trial (SELECT) in October 2008 ahead of schedule because of the failure to demonstrate an efficacy of selenomethionine (SeMet) for PCa prevention in North American men and a slight but non- statistically significant increase in diabetes risk. Because of the metabolic and biochemical differences between SeMet and other Se forms, the failure of SeMet in the SELECT study should and cannot be equated to all Se forms as ineffective for PCa prevention. We have compelling evidence that daily oral supplementation of putative precursors of methylselenol, methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC), inhibit the in vivo growth of human PCa xenograft in athymic nude mice whereas SeMet does not; and that MSeA and MSeC inhibit primary carcinogenesis in the transgenic adenocarcinoma mouse prostate (TRAMP) model with significant survival benefit. While these in vivo data suggest these second-generation Se compounds (vs. SeMet) as promising bioactive supplements for PCa prevention and merit consideration for future translational studies, inherent limitations of the TRAMP model temper the value of these data for human translatability. Therefore, in this R21 proposal in response to PA-07-362, we hypothesize that MSeA, as a representative of second-generation Se, inhibits/prevents PCa progression from PIN to adenocarcinoma through targeting Akt signaling pathway in a Pten-deficiency mouse model. Two specific aims are proposed. Aim 1: To determine the efficacy of MSeA in preventing Pten deletion-driven PCa development in vivo. We will generate prostate-specific Pten-deletion (Pten-/-) mice using Cre-loxP technique. The wild type Pten+/+ mice and Pten-/- mice will be treated with 2 dosages of MSeA at 7 weeks of age (WOA). At 12 WOA and 27 WOA, 10 mice of each group will be sacrificed. An extensive histopathology survey will determine the early lesion responses. Tissue samples will be banked for verifying molecular targeting (Aim2). Additional cohorts (n=20) of Pten-/- mice will be used to assess the beneficial impact of MSeA on their survival, PCa burden (weight, number) and metastasis. Aim 2: To test whether the preventive efficacy of MSeA is associated with a suppression of AKT signaling pathway. We will measure AKT phosphorylation and its downstream targets by immunohistochemistry and Western Blot in prostate tissues collected at the first 2 endpoints and correlate them to indices of cell proliferation and cell death and overall survival benefit. Impacts of the results: The results will provide "proof-of-principle data" regarding the usefulness of Pten-/- model for assessing MSeA as a bioactive dietary supplement in vivo and lay the ground work for future R01/P01 projects for developing this and other second-generation Se for molecular pathway-targeted PCa prevention. PUBLIC HEALTH RELEVANCE: The ill-reputed selenomethionine in the Selenium and vitamin E Cancer prevention Trial (SELECT) study has brought a lot of negative publicities on the whole research field of selenium-cancer prevention and treatment. Rigorous studies as proposed here that use a clinically relevant pre-clinical model and a judicious choice of selenium agents with compelling mechanistic rationale and support (unlike the case with SeMet for SELECT) are essential and necessary to produce relevant data to support continued work to realize the full health benefits of the second-generation selenium and change perceptions and understanding of scientists and the public alike on selenium's merits.

描述(由申请人提供)：前列腺癌的化学预防是从根本上解决前列腺癌(PCA)问题的一种看似合理和必要的方法。先前的研究表明，补充硒(Se)可以预防或延缓人类前列腺癌的发生。然而，NCI于2008年10月提前停止了硒和维生素E癌症预防试验(SELECT)，原因是未能证明硒蛋氨酸(SEMET)对北美男性预防前列腺癌的有效性，而且糖尿病风险略有增加，但没有统计意义上的显著增加。由于SEMet和其他Se形式之间的代谢和生化差异，SEMet在选择研究中的失败应该也不能等同于所有Se形式对预防前列腺癌无效。我们有令人信服的证据表明，每日口服甲基硒醇前体、甲基硒酸(MSEA)和硒-甲基硒半胱氨酸(MSEC)可以抑制人前列腺癌裸鼠移植瘤的体内生长，而SeMet不会；MSEA和MSEC在转基因前列腺癌小鼠前列腺癌(TRAMP)模型中抑制原发癌变，具有显著的生存益处。虽然这些体内数据表明，这些第二代Se化合物(vs.seMet)是预防前列腺癌的有前景的生物活性补充剂，值得考虑用于未来的翻译研究，但TRAMP模型的固有局限性削弱了这些数据对人类可译性的价值。因此，在这个针对PA-07-362的R21提案中，我们假设MSEA作为第二代Se的代表，通过靶向Akt信号通路，在Pten缺乏的小鼠模型中抑制/阻止PIN向腺癌的PCA进展。提出了两个具体目标。目的1：确定MSEA在体内预防Pten缺失驱动的前列腺癌发生的效果。我们将使用Cre-loxP技术产生前列腺特异性Pten缺失(Pten-/-)小鼠。野生型Pten+/+小鼠和Pten-/-小鼠在7周龄时接受两种剂量的MSEA治疗(WOA)。12周龄和27周龄处死小鼠，每组10只。广泛的组织病理学检查将确定早期病变反应。组织样本将被储存以验证分子靶向(AIM2)。Pten-/-小鼠的额外队列(n=20)将用于评估MSEA对它们的生存、PCA负担(体重、数量)和转移的有益影响。目的：验证MSEA的预防作用是否与抑制AKT信号通路有关。我们将通过免疫组织化学和Western Blot检测前两个终点收集的前列腺组织中的AKT磷酸化及其下游靶点，并将它们与细胞增殖和细胞死亡指数以及总体生存受益指数相关联。结果的影响：该结果将提供关于Pten-/-模型在体内评估MSEA作为生物活性膳食补充剂的有用性的“原则证明数据”，并为未来的R01/P01项目奠定基础，开发这种和其他第二代Se用于分子通路靶向PCa的预防。 公共卫生相关性：硒和维生素E癌症预防试验(SELECT)研究中的硒蛋氨酸臭名昭著，给整个硒癌症预防和治疗研究领域带来了许多负面宣传。这里建议的严格研究使用临床相关的临床前模型和明智地选择具有令人信服的机制基础和支持的硒制剂(不像SEMET用于选择的情况)，对于产生相关数据以支持实现第二代硒的全部健康益处的继续工作是必要和必要的，并改变科学家和公众对硒的优点的看法和理解。