Prevention of PTEN deletion driven prostate cancer by selenium

硒预防 PTEN 缺失导致的前列腺癌

基本信息

批准号：
8206703
负责人：
YIBIN DENG
金额：
$ 16.58万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-15 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8206703
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 public health relevance research study response selenomethylselenocysteine translational study tumor progression

项目摘要

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）问题的合理且必要的方法。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)，因为未能证明硒代蛋氨酸 (SeMet) 对北美男性预防 PCa 的功效，并且有轻微但无统计学意义。糖尿病风险增加。由于 SeMet 和其他 Se 形式之间的代谢和生化差异，SeMet 在 SELECT 研究中的失败应该且不能等同于所有 Se 形式对 PCa 预防无效。我们有令人信服的证据表明，每日口服补充假定的甲基硒醇、甲基硒酸 (MSeA) 和 Se-甲基硒代半胱氨酸 (MSeC) 前体，可抑制无胸腺裸鼠体内人 PCa 异种移植物的生长，而 SeMet 则不会； MSeA 和 MSeC 抑制转基因小鼠前列腺腺癌 (TRAMP) 模型中的原发性癌变，具有显着的生存益处。虽然这些体内数据表明这些第二代 Se 化合物（相对于 SeMet）作为预防 PCa 的有前景的生物活性补充剂，值得未来的转化研究考虑，但 TRAMP 模型的固有局限性削弱了这些数据对人类可翻译性的价值。因此，在针对PA-07-362的R21提案中，我们假设MSeA作为第二代Se的代表，在Pten缺陷小鼠模型中通过靶向Akt信号通路抑制/阻止PCa从PIN向腺癌的进展。提出了两个具体目标。目标 1：确定 MSeA 在体内预防 Pten 缺失驱动的 PCa 发育的功效。我们将使用 Cre-loxP 技术生成前列腺特异性 Pten 缺失 (Pten-/-) 小鼠。野生型Pten+/+小鼠和Pten-/-小鼠将在7周龄(WOA)时用2个剂量的MSeA治疗。在12 WOA和27 WOA时，每组将处死10只小鼠。广泛的组织病理学调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）。其他 Pten-/- 小鼠组 (n=20) 将用于评估 MSeA 对它们的生存、PCa 负担（重量、数量）和转移的有益影响。目标 2：测试 MSeA 的预防功效是否与 AKT 信号通路的抑制相关。我们将通过免疫组织化学和蛋白质印迹法测量前 2 个终点收集的前列腺组织中的 AKT 磷酸化及其下游靶标，并将它们与细胞增殖和细胞死亡指数以及总体生存获益相关联。结果的影响：结果将提供有关 Pten-/- 模型评估 MSeA 作为体内生物活性膳食补充剂的有效性的“原理验证数据”，并为未来开发该模型的 R01/P01 项目奠定基础。和其他用于分子途径靶向 PCa 预防的第二代 Se。公共健康相关性：硒和维生素 E 癌症预防试验 (SELECT) 研究中声誉不佳的硒代蛋氨酸给整个硒癌症预防和治疗研究领域带来了很多负面宣传。这里提出的严格研究，使用临床相关的临床前模型，并明智地选择具有令人信服的机制原理和支持的硒制剂（与用于 SELECT 的 SeMet 的情况不同），对于产生相关数据以支持继续工作以实现这一目标是必要和必要的。第二代硒的全面健康益处，并改变科学家和公众对硒优点的看法和理解。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Methylseleninic Acid Superactivates p53-Senescence Cancer Progression Barrier in Prostate Lesions of Pten-Knockout Mouse.

DOI：
10.1158/1940-6207.capr-15-0236
发表时间：
2016-01
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
0
作者：
Wang L;Guo X;Wang J;Jiang C;Bosland MC;Lü J;Deng Y
通讯作者：
Deng Y

Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer.

DOI：
10.1016/j.ebiom.2016.03.022
发表时间：
2016-05
期刊：
EBioMedicine
影响因子：
11.1
作者：
Wang L;Wang J;Xiong H;Wu F;Lan T;Zhang Y;Guo X;Wang H;Saleem M;Jiang C;Lu J;Deng Y
通讯作者：
Deng Y