S-Adenosylmethionine in Protein Posttranslational Modifications and HCC Treatment

S-腺苷甲硫氨酸在蛋白质翻译后修饰和 HCC 治疗中的作用

• 批准号: 8987417
• 负责人: Shelly Chi-Loo Lu
• 金额: $ 39.38万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8987417
• 关键词: Adult; Affect; Aging; Anabolism; Apoptotic; Asia; BAY 54-9085; Behavior; Biological; Cancer cell line; Catabolism; Cell division; Cell membrane; Cells; Cessation of life; Chemopreventive Agent; Chronic; Colon Carcinoma; Complex; Data; Development; Dose; Effectiveness; Enzymes; Epithelial Cells; Europe; Exhibits; Extrahepatic; Genes; Genomic Instability; Goals; Growth; Health; Hepatic; Homeostasis; Human; Inflammatory; Injury to Liver; Intestines; Isoenzymes; Knock-out; Knockout Mice; Knowledge; Lead; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Mammalian Cell; Mediating; Messenger RNA; Metabolism; Methionine; Methylation; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Oral; Oxidative Stress; Pathway interactions; Patients; Pharmacologic Actions; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Polyamines; Population; Post-Translational Protein Processing; Prevention; Primary carcinoma of the liver cells; Process; Proteins; Proteome; Proteomics; Public Health; Reaction; Receptor Protein-Tyrosine Kinases; Recurrence; Reporting; Role; S-Adenosylmethionine; STK11 gene; Signal Pathway; Signal Transduction; Specificity; Specimen; Steatohepatitis; Stem cells; Technology; Tissues; Tumor Tissue; Ubiquitin-Conjugating Enzymes; United States; Work; adenylate kinase; cancer cell; cancer stem cell; chronic liver disease; cytokine; design; dimer; glycine N-methyltransferase; interest; methionine adenosyltransferase; mouse model; public health relevance; treatment effect; tumorigenesis

 DESCRIPTION (provided by applicant): S-adenosylmethionine (SAMe) is the principal biological methyl donor, precursor of polyamines and GSH. SAMe is made in all mammalian cells via the enzyme methionine adenosyltransferase (MAT). In liver, SAMe biosynthesis is carried out by MATI/III isoenzymes (tetramer and dimer of a1 encoded by MAT1A). Patients with chronic liver disease have reduced hepatic MAT activity and SAMe levels. We showed that mice lacking MAT1A exhibit increased oxidative stress and develop hepatocellular carcinoma (HCC) spontaneously. SAMe is widely available in the United States as a health supplement and is used therapeutically in Europe and Asia. Despite its wide usage, the molecular mechanisms of its actions are largely unclear. We have reported that many of SAMe's actions are mimicked by its metabolite methylthioadenosine (MTA). In particular, both are selectively pro-apoptotic in liver and colon cancer cells and inhibit the expression of pro-inflammatory cytokines. SAMe is a methyl donor but MTA inhibits methylation. Our accumulated results show three key post- translational protein modifications, methylation, sumoylation and phosphorylation, are dysregulated in the setting of chronic hepatic SAMe depletion that can be corrected by SAMe. There is interesting crosstalk and interplay between these pathways, which are frequently dysregulated in HCC, and are targeted by pharmacologic administration of SAMe and MTA. This application is designed to examine how hepatic SAMe deficiency impacts on these protein posttranslational modifications (PTMs) and how pharmacologic SAMe/MTA work on these pathways. Four specific aims are proposed: 1. Define the effect of SAMe depletion on sumoylation machinery and protein PTMs. We will elucidate the effect of hepatic SAMe deficiency on sumoylation machinery and changes in the SUMO-, Ser/Thr-phospho- and methyl-proteomes. 2. Examine how SAMe depletion affects activity of MAPKs, receptor tyrosine kinases (RTKs) and Tyr-phospho- proteome. Our preliminary data indicate the activity of several MAPKs and RTKs are affected by SAMe level. We will elucidate the mechanisms involved and how SAMe level impacts on the Tyr-phosphoproteome. 3. Examine pharmacologic SAMe and MTA actions on protein PTMs. Pharmacologic SAMe and MTA reduce ubiquitin-conjugating enzyme 9 (Ubc9), the sole E2 enzyme for sumoylation, and inhibit ERK and Akt signaling. We will determine the molecule responsible, mechanisms involved, and examine their effects on protein PTMs in liver cancer cell lines and normal human intestinal epithelial cells. 4. Examine effectiveness of SAMe/MTA or sorafenib alone or in combination in HCC treatment. We will examine the efficacy of oral SAMe or MTA ± sorafenib versus sorafenib alone in the treatment of HCC growth and recurrence. The effect of these treatments on protein PTMs will also be examined in tumor tissues. Successful completion of these aims should enhance our knowledge of the complex interplay between the protein PTMs that is regulated by SAMe and assess SAMe/MTA efficacy in HCC treatment, topics that are highly relevant to public health.

 描述（由应用提供）：S-腺苷甲硫代氨酸（相同）是主要的生物甲基供体，多胺和GSH的前体。所有哺乳动物细胞都通过蛋氨酸腺苷转移酶（MAT）制成。在肝脏中，Mati/III同工酶（由MAT1A编码的A1的四聚体和二聚体）进行相同的生物合成。慢性肝病患者的肝MAT活性降低和相同水平。我们表明，缺乏MAT1A暴露的小鼠氧化应激增加并发育于发育中的肝细胞癌（HCC）。在美国，作为健康补充剂也广泛使用，在欧洲和亚洲使用治疗。尽管使用广泛，但其作用的分子机制在很大程度上尚不清楚。我们报道说，许多相同的作用都被其代谢物甲基腺苷（MTA）模仿。特别是，两者在肝脏和结肠癌细胞中有选择性地促凋亡，并抑制促炎性细胞因子的表达。同样是甲基供体，但MTA抑制甲基化。我们的累积结果表明，在慢性肝耗尽相同的耗竭的情况下，可以通过相同的相同校正的情况下，三种关键的翻译后蛋白质修饰，甲基化，sumoylation和磷酸化失调。这些途径之间存在有趣的串扰和相互作用，这些途径在HCC中经常失调，并且由药理学给予相同和MTA的靶向。该应用旨在检查肝素相同的缺乏对这些蛋白质翻译后修饰（PTMS）的影响如何以及药理学在这些途径上的相同/MTA如何起作用。提出了四个具体目的：1。定义相同部署对Sumoylation机械和蛋白质PTM的影响。我们将阐明肝素相同缺陷对Sumoylation机制的影响以及SUMO，Ser/Thr-磷酸和甲基蛋白质体的变化。 2。检查相同的耗竭如何影响MAPK，受体酪氨酸激酶（RTK）和Tyr-phospho-蛋白质组的活性。我们的初步数据表明几个MAPK和RTK的活性受同一级别的影响。我们将阐明机制3。检查药理学对蛋白质PTM的相同和MTA作用。药理学相同和MTA降低了泛素 - 偶联酶9（UBC9），唯一的E2酶进行Sumoylation，并抑制ERK和AKT信号传导。我们将确定涉及的分子，机制，并检查其对肝癌细胞系和正常人肠上皮细胞中蛋白质PTM的影响。 4。单独检查相同/MTA或索拉非尼的有效性，或在HCC治疗中检查。我们将检查口服相同或MTA±索拉非尼与索拉非尼在HCC生长和复发方面的有效性。这些治疗对蛋白质PTM的影响也将在肿瘤组织中进行检查。这些目标的成功完成应增强我们对受相同调节并评估HCC治疗中相同/MTA效率的蛋白质PTM之间复杂相互作用的知识，这与公共卫生高度相关。