Intervention of Pancreatic Oncogenic Pathways with Dietary Tocotrienol

用膳食生育三烯酚干预胰腺致癌途径

• 批准号: 8112675
• 负责人: Mokenge P. Malafa
• 金额: $ 62.91万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112675
• 关键词: ATP phosphohydrolase; Accounting; Actinin; Address; Affinity Chromatography; Antineoplastic Agents; Antioxidants; Apoptosis; Barley; Binding; Binding Proteins; Biochemical; Biodiversity; Biological; Biological Assay; Biological Markers; Cancer cell line; Canned Foods; Cell Cycle Progression; Cell Proliferation; Cells; Cereals; Chemoprevention; Chemopreventive Agent; Cholesterol; Clinical; Consumption; Data; Development; Dietary Fiber; Dose; Down-Regulation; Engineering; Epidemiologic Studies; Event; Excision; Experimental Models; Exportins; Food; Genes; Goals; Growth; Health; Human; Immunohistochemistry; In Vitro; Incidence; Intake; Intervention; K-ras Oncogene; Laboratories; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Measurement; Mediating; Micronutrients; Minerals; Modeling; Molecular; Mus; Mutation; Nuclear Export; Nutrient; Nutritional; Oats; Oncogenes; Oncogenic; Oral Administration; Other Genetics; PI3K/AKT; Pancreas; Pancreatectomy; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Physiological; Prevention; Prevention therapy; Process; Property; Protein p53; Proteins; Ras Signaling Pathway; Reporting; Research; Rice; Risk; Role; Safety; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Testing; Tissues; Tocotrienols; Toxic effect; Translating; Tumor Suppressor Genes; Tumor Tissue; Up-Regulation; Vitamin E; Vitamins; base; bioactive food component; cancer cell; carcinogenesis; caspase-8; chemical carcinogenesis; delta tocotrienol; drebrins; fruits and vegetables; in vivo; insight; malignant breast neoplasm; man; neoplastic cell; novel; pancreatic cancer cells; pancreatic neoplasm; pancreatic tumorigenesis; prevent; ras Oncogene; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Epidemiological studies suggest an inverse association between the intake of whole-grain cereal food and the risk of pancreatic cancer, one of the deadliest malignancies. However, it remains unclear whether a specific bioactive component of cereal food can be used to modify the pancreatic cancer process. Tocotrienols, the predominant vitamin E compounds in cereal foods, have been proposed as potential anticancer agents due to their clinical safety as well as their chemopreventive activity and inhibitory effects on cancer cells in experimental models. We have observed that 4-tocotrienol inhibits the growth and survival of pancreatic cancer cells in vitro and in vivo. Our preliminary study also shows accumulation of bioactive concentrations of 4-tocotrienol in the pancreatic tissue of mice following oral administration. These findings combined with its superior efficacy and safety, make 4-tocotrienol a promising anticancer bioactive component of cereal food and constitute a compelling argument to study its mechanism of action in pancreatic oncogenesis. We propose to test two hypotheses: a) that 4-tocotrienol is a chemopreventive micronutrient against pancreatic cancer, and b) that 4-tocotrienol inhibits the effectors of oncogenic Ras signal transduction pathways in the pancreas and that this effect accounts for its antitumor activity. Oncogenic Ras activation is a key event in pancreatic carcinogenesis. Our preliminary data indicate that 4- tocotrienol strongly inhibits several effectors of activated Ras in pancreatic cancer cells such as down regulation of the Mek/Erk and PI3K/Akt mitogenic and tumor survival signaling pathways and up regulation of p27. Our specific aims are: 1) To determine in the PDX-1-Cre;LSL-KRASG12D genetically engineered model of pancreatic cancer the efficacy of 4-tocotrienol against pancreatic carcinogenesis and elucidate its in vivo effect on Mek/Erk and PI3K/Akt signaling pathways. Specifically, we will determine the incidence and progression of pancreatic intraepithelial neoplasias; inhibition of Mek/Erk and PI3K/Akt activation; effects on cell proliferation, apoptosis, and relevant Mek/Erk and PI3K/Akt dependent genes that mediate this effect. 2) To elucidate the mechanistic basis for 4-tocotrienol induction of p27. Exportin-dependent nuclear export is linked to the degradation of p27, an important regulator of cell cycle progression in pancreatic cancer cells. Our preliminary data indicates that 4-tocotrienol binds to exportin and induces accumulation of p27 in pancreatic cancer cells. We will determine whether p27 is regulated by 4-tocotrienol/exportin binding. 3) To perform a phase 1 a/b trial to investigate whether consumption of 4-tocotrienol for 2 weeks prior to pancreatectomy will induce p27 and alter Mek/Erk and PI3K/Akt signaling pathways leading to an inhibition of proliferation and increase in apoptosis in the pancreas. Results of the proposed research will provide significant insight into the utilization of dietary tocotrienol in the prevention and therapy of pancreatic cancer. PUBLIC HEALTH RELEVANCE The objective of this project is to translate novel laboratory discoveries about the bioactive food component, delta-tocotrienol, to the prevention and treatment of pancreatic cancer, one of the deadliest malignancies known to man. Numerous epidemiological studies have indicated that consumption of whole-grain cereal foods reduce the risk of pancreatic cancer. However, it remains unclear whether a specific bioactive component of cereal food can be used to prevent the pancreatic cancer process. Tocotrienols, the predominant vitamin E compounds in cereal foods, have been proposed as potential anticancer agents due to their safety as well as their protective activity against cancer cells in experimental models. We have observed that 4- tocotrienol inhibits the growth and survival of pancreatic cancer cells by blocking some of the important signals triggered by the Ras oncogene which is the key oncogene that is implicated in the development of >90% of pancreatic cancers. These findings combined with its superior efficacy and safety, make 4-tocotrienol a promising anticancer bioactive component of cereal food and constitute a compelling argument to investigate its action in pancreatic tumor development. We propose to test the hypotheses that 4-tocotrienol is a protective micronutrient against pancreatic cancer by inhibiting the effectors of Ras signaling pathways. Specifically, we plan to determine 4-tocotrienol efficacy in the Ras genetically engineered model of pancreatic cancer. We have discovered that 4- tocotrienol binds to some novel proteins with important function in regulating the growth signals in cells. We plan to conduct detailed studies to understand how these tocotrienol binding proteins contribute to the bioactivity of tocotrienols against cancer cells. Finally, we will conduct a hypothesis driven phase 1 a/b trial to investigate whether consumption of 4-tocotrienol for 2 weeks prior to pancreatectomy will alter ras signaling pathways leading to an inhibition of proliferation and increase in apoptosis in human pancreatic tumors. The results from these studies will advance our understanding of how a bioactive food component such as delta-tocotrienol can be exploited for the prevention and treatment of pancreatic cancer.

描述（由申请人提供）： 流行病学研究表明，全麦谷物食品的摄入量与胰腺癌（最致命的恶性肿瘤之一）的风险呈负相关。然而，目前还不清楚谷物食品的特定生物活性成分是否可以用于改变胰腺癌的过程。生育三烯酚是谷类食品中主要的维生素E化合物，由于其临床安全性以及在实验模型中对癌细胞的化学预防活性和抑制作用，已被提议作为潜在的抗癌剂。我们已经观察到4-生育三烯酚在体外和体内抑制胰腺癌细胞的生长和存活。我们的初步研究还显示，口服给药后，小鼠胰腺组织中积累了生物活性浓度的4-生育三烯酚。这些发现结合其上级功效和安全性，使4-生育三烯酚成为谷物食品中有前途的抗癌生物活性成分，并构成研究其在胰腺肿瘤发生中的作用机制的令人信服的论据。我们提出了两个假设：a）4-生育三烯酚是一种化学预防性微量营养素，对胰腺癌，和B）4-生育三烯酚抑制胰腺中致癌Ras信号转导通路的效应，这种效果占其抗肿瘤活性。致癌性Ras激活是胰腺癌发生的关键事件。我们的初步数据表明，4-生育三烯酚强烈抑制胰腺癌细胞中激活的Ras的几种效应物，如Mek/Erk和PI 3 K/Akt促有丝分裂和肿瘤存活信号通路的下调以及p27的上调。我们的具体目标是：1）在胰腺癌的PDX-1-Cre; LSL-KRASG 12 D基因工程模型中确定4-生育三烯酚对胰腺癌发生的功效，并阐明其对Mek/Erk和PI 3 K/Akt信号传导途径的体内作用。具体而言，我们将确定胰腺上皮内瘤形成的发生率和进展; Mek/Erk和PI 3 K/Akt激活的抑制;对细胞增殖、凋亡的影响，以及介导这种影响的相关Mek/Erk和PI 3 K/Akt依赖基因。2)阐明4-生育三烯酚诱导p27的机制基础。Exportin依赖的核输出与p27的降解有关，p27是胰腺癌细胞中细胞周期进程的重要调节因子。我们的初步数据表明，4-生育三烯酚结合exportin和诱导胰腺癌细胞中的p27积累。我们将确定p27是否受4-生育三烯酚/exportin结合的调控。3)进行一项1a/B期试验，以研究胰腺切除术前2周服用4-生育三烯酚是否会诱导p27并改变Mek/Erk和PI 3 K/Akt信号通路，从而抑制胰腺增殖并增加胰腺凋亡。该研究结果将为膳食生育三烯酚在胰腺癌预防和治疗中的应用提供重要的参考。公共卫生相关性本项目的目标是将实验室关于生物活性食品成分δ-生育三烯酚的新发现转化为胰腺癌的预防和治疗，胰腺癌是人类已知的最致命的恶性肿瘤之一。许多流行病学研究表明，食用全谷物食品可以降低胰腺癌的风险。然而，目前还不清楚谷物食品的特定生物活性成分是否可以用于预防胰腺癌。生育三烯酚是谷类食品中主要的维生素E化合物，由于其安全性以及在实验模型中对癌细胞的保护活性，已被提议作为潜在的抗癌剂。我们已经观察到，4-生育三烯酚通过阻断Ras癌基因触发的一些重要信号来抑制胰腺癌细胞的生长和存活，Ras癌基因是与>90%的胰腺癌的发展有关的关键癌基因。这些发现结合其上级功效和安全性，使4-生育三烯酚成为谷物食品中有前途的抗癌生物活性成分，并构成了研究其在胰腺肿瘤发展中的作用的令人信服的论据。我们建议测试的假设，4-生育三烯酚是一种保护性微量营养素对胰腺癌的抑制Ras信号通路的效应。具体来说，我们计划确定4-生育三烯酚在Ras基因工程胰腺癌模型中的疗效。我们发现4-生育三烯酚与一些新的蛋白质结合，这些蛋白质在调节细胞生长信号中具有重要功能。我们计划进行详细的研究，以了解这些生育三烯酚结合蛋白如何有助于生育三烯酚对癌细胞的生物活性。最后，我们将进行一项假设驱动的1a/B期试验，以研究胰腺切除术前2周摄入4-生育三烯酚是否会改变ras信号通路，从而抑制人胰腺肿瘤的增殖并增加凋亡。这些研究的结果将促进我们对生物活性食品成分（如δ-生育三烯酚）如何用于预防和治疗胰腺癌的理解。