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: 7690215
• 负责人: Mokenge P. Malafa
• 金额: $ 67.7万
• 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/7690215
• 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; Breast; 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; Food; Genes; Goals; Growth; Human; Immunohistochemistry; In Vitro; Incidence; Intake; Intervention; K-ras Oncogene; Laboratories; Link; Liver; Malignant - descriptor; Malignant Neoplasms; 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; fruits and vegetables; in vivo; insight; man; neoplastic cell; novel; pancreatic neoplasm; pancreatic tumorigenesis; prevent; public health relevance; 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，摄入全谷类食物与患胰腺癌的风险呈负相关，胰腺癌是最致命的恶性肿瘤之一。然而，目前还不清楚谷类食品中的特定生物活性成分是否可以用来改变胰腺癌的过程。生育三烯醇是谷物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和抑制作用，已被认为是潜在的抗癌药物。我们在体内外观察到4-生育三烯醇对胰腺癌细胞的生长和存活有抑制作用。我们的初步研究还显示，口服给药后，4-生育三烯醇在小鼠胰腺组织中积累了生物活性浓度。这些发现与其优越的有效性和安全性相结合，使4-生育三烯醇成为一种有前景的谷类食品抗癌生物活性成分，并为研究其在胰腺癌发生中的作用机制提供了有力的证据。我们提出了两个假设：a)4-生育三烯醇是一种抗胰腺癌的化学预防微量营养素，b)4-生育三烯醇抑制了胰腺中致癌RAS信号转导通路的效应，这一作用是其抗肿瘤活性的原因。致癌RAS激活是胰腺癌发生过程中的关键事件。我们的初步数据表明，4-生育三烯醇强烈抑制胰腺癌细胞中激活的RAS的几个效应分子，如下调MEK/Erk和PI3K/Akt有丝分裂和肿瘤生存信号通路，上调p27。1)在PDX-1-CRE；LSL-KrasG12D胰腺癌基因工程模型中，检测4-生育三烯醇对胰腺癌发生的作用，并阐明其在体内对MEK/Erk和PI3K/Akt信号通路的影响。具体地说，我们将确定胰腺上皮内肿瘤的发生和发展；抑制MEK/Erk和PI3K/Akt的激活；对细胞增殖、凋亡的影响，以及介导这一效应的相关MEK/Erk和PI3K/Akt依赖基因。2)阐明4-生育三烯醇诱导p27基因表达的机制。依赖Exportin的核输出与p27的降解有关，p27是胰腺癌细胞细胞周期进展的重要调节因子。我们的初步数据表明，4-生育三烯醇与Exportin结合，并诱导胰腺癌细胞中p27的积聚。我们将确定p27是否受4-生育三烯醇/出口蛋白结合的调节。3)进行a/b期实验，研究胰腺切除前2周应用4-生育三烯醇是否会诱导p27，并改变MEK/Erk和PI3K/Akt信号通路，导致胰腺增殖抑制和细胞凋亡增加。建议的研究结果将为膳食生育三烯醇在胰腺癌预防和治疗中的应用提供重要的见解。公共卫生相关性该项目的目标是将关于生物活性食品成分--β-生育三烯醇的最新实验室发现转化为预防和治疗胰腺癌，胰腺癌是人类已知的最致命的恶性肿瘤之一。大量流行病学研究表明，食用全麦谷类食品可降低患胰腺癌的风险。然而，目前尚不清楚谷类食品中的特定生物活性成分是否可以用于预防胰腺癌过程。生育三烯醇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作用，已被认为是潜在的抗癌药物。我们观察到，4-生育三烯醇通过阻断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%胰腺癌的发生有关的关键癌基因。这些发现与其优越的有效性和安全性相结合，使4-生育三烯醇成为一种有前景的谷类食品抗癌生物活性成分，并构成了研究其在胰腺肿瘤发生中作用的有力论据。我们建议通过抑制RAS信号通路的效应器来检验4-生育三烯醇是一种抗胰腺癌的微量营养素的假说。具体地说，我们计划确定4-生育三烯醇在RAS基因工程胰腺癌模型中的疗效。我们发现4-生育三烯醇与一些新的蛋白质结合，在调节细胞内的生长信号方面具有重要的功能。我们计划进行详细的研究，以了解这些生育三烯醇结合蛋白如何有助于生育三烯醇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，以调查胰腺切除前2周服用4-生育三烯醇是否会改变ras信号通路，从而抑制人胰腺肿瘤的增殖和增加细胞凋亡。这些研究的结果将促进我们对生物活性食品成分，如β-生育三烯醇如何被用于预防和治疗胰腺癌的理解。