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（由申请人提供）：S-腺苷甲硫氨酸（SAMe）是主要的生物甲基供体，是多胺和GSH的前体，SAMe在所有哺乳动物细胞中通过甲硫氨酸腺苷转移酶（MAT）在肝脏中进行生物合成。 MATI/III 同工酶（MAT1A 编码的 a1 四聚体和二聚体）患有慢性肝病。我们发现，缺乏 MAT1A 的小鼠会表现出氧化应激增加并自发发展为肝细胞癌 (HCC)，SAMe 在美国作为保健补充剂广泛使用，并在欧洲和亚洲用于治疗。其用途广泛，但其作用的分子机制在很大程度上尚不清楚。我们已经报道，SAMe 的许多作用是由其代谢物甲硫腺苷 (MTA) 模仿的。在肝癌和结肠癌细胞中选择性促凋亡并抑制促炎细胞因子的表达。在可通过 SAMe 纠正的慢性肝 SAMe 耗竭的情况下，这些通路之间存在有趣的串扰和相互作用，这些通路在 HCC 中经常失调，并且是 SAMe 的靶点。 SAMe 和 MTA 的药理学管理 该应用旨在检查肝脏 SAMe 缺乏如何影响这些蛋白质翻译后修饰 (PTM) 以及 SAMe/MTA 如何对这些途径发挥作用： 1. 定义 SAMe 的作用。 sumoylation 机制和蛋白质 PTM 的消耗我们将阐明肝脏 SAMe 缺乏对 sumoylation 机制以及 SUMO-、Ser/Thr-磷酸化和变化的影响。 2. 检查 SAMe 消耗如何影响 MAPK、受体酪氨酸激酶 (RTK) 和酪氨酸磷酸蛋白组的活性。我们的初步数据表明，几种 MAPK 和 RTK 的活性受到 SAMe 水平的影响。涉及以及 SAMe 水平如何影响 Tyr-磷酸化蛋白质组 3. 检查 SAMe 和 MTA 对蛋白质 PTM 的药理学作用。 MTA 减少泛素结合酶 9 (Ubc9)（唯一的苏酰化 E2 酶），并抑制 ERK 和 Akt 信号传导。我们将确定负责的分子、相关机制，并检查它们对肝癌细胞系和正常人中蛋白质 PTM 的影响。 4. 检查 SAMe/MTA 或索拉非尼单独或联合治疗 HCC 的有效性 我们将检查口服 SAMe 或 MTA ± 索拉非尼的疗效。索拉非尼单独治疗 HCC 生长和复发也将在肿瘤组织中检查这些治疗对蛋白质 PTM 的影响，这些目标的成功完成应该会增强我们对 SAMe 和 调节的蛋白质 PTM 之间复杂相互作用的了解。评估 SAMe/MTA 在 HCC 治疗中的疗效，这些主题与公共卫生高度相关。