Role of Hydrogen Sulfide in Colorectal Tumors

硫化氢在结直肠肿瘤中的作用

基本信息

批准号：
8708260
负责人：
MARK R HELLMICH
金额：
$ 31.24万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-19 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708260
关键词：
3-Mercaptopyruvate sulfurtransferase Address Aminooxyacetic Acid Animal Model Animals Antineoplastic Agents Apoptosis Applications Grants Area Bioenergetics Biological Biological Process Biological Response Modifier Therapy Cancer Biology Cancer Patient Cancer cell line Cecum Cell Line Cell Proliferation Cells Characteristics Clinical Clinical Trials Colon Carcinoma Colorectal Cancer Colorectal Neoplasms Complex Cystathionine Data Development Electron Transport Electrons Enzymes Epigenetic Process Equilibrium Foundations GOT2 gene Gases Generations Genetic Glycolysis Growth Heterotopic Transplantation Human Human Biology Hydrogen Sulfide Immune In Vitro Inflammatory KRAS2 gene Malate-Aspartate Shuttle Pathway Mediating Mediator of activation protein Mitochondria Modeling Molecular Movement Mus Mutation NADH Neoplasm Metastasis Outcome Oxidative Phosphorylation PTEN gene Pathway interactions Patients Phenotype Phosphotransferases Post-Translational Protein Processing Pre-Clinical Model Production Proteins Publishing Relative (related person)Role Series Signal Transduction Testing Therapeutic Therapeutic Agents Tumor Angiogenesis Tumor Cell Invasion Tumor Tissue Up-Regulation Work Xenograft Model Xenograft procedure aerobic glycolysis angiogenesis anti-cancer therapeutic base cancer cell cancer therapy cell growth cell motility drug development drug efficacy electron donor extracellular human tissue in vivo inhibitor/antagonist innovation malignant colon tumor metastatic colorectal migration neoplastic cell novel novel therapeutics paracrine pre-clinical public health relevance research study small hairpin RNA subcutaneous sulfhydration theories translational study tumor tumor growth tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): This revised grant application focuses on the role of the endogenous gaseous biological mediator hydrogen sulfide (H2S) in colorectal cancer. Based on multiple lines of novel data, we have developed the novel hypothesis that selective upregulation of cystathionine-¿-synthase (CBS) and the subsequent production of H2S in colonic cancer cells serves as a pro-survival factor by stimulating tumor cell bioenergetics, growth, proliferation, migration and invasion. In order to explore this concept, we will pursue the following Aims: #1. To characterize the molecular mechanisms by which the CBS/H2S axis promotes tumor cell bioenergetics and tumor cell proliferation; #2. To determine the molecular mechanisms by which the CBS/H2S axis promotes tumor cell migration, invasion and metastasis; and #3. To evaluate the effect of the CBS inhibitor aminooxyacetic acid (AOAA) in human colorectal cancer, in a translationally relevant animal model utilizing patient-derived xenografts (PDTX) in combination with current clinical anticancer therapeutic agents. Taken together, the current project will utilize human colonic cancer tissues, human colonic cancer cell lines and tumor-bearing mice subjected to heterotopic transplantation of human colon cancer lines or patient-derived xenografts. To address the role of CBS, a combination of genetic (CBS silencing) and pharmacological (CBS inhibitors) approaches will be used. Outcome variables will include parameters of bioenergetics (oxidative phosphorylation, mitochondrial electron transport, glycolysis, GAPDH activity), cell proliferation, cell growth (including activation of pr-inflammatory/pro-growth kinase pathways), tumor cell migration, tumor cell invasion, angiogenesis and metastasis in vitro and in vivo. The role of sulfhydration (a specific H2S-mediated posttranslational protein modification) will be also explored on relevant protein targets (GAPDH, PTEN, PI3K). The final, translational aim will contain studies of potential therapeutic relevance, by testing the anticancer effect of CBS inhibitors, in summary, the current project entails a comprehensive approach to test the importance of CBS/H2S a novel pathway in colorectal cancer, and incorporates early translational work to explore its potential utility as a target for anticancer therapy.

描述（通过应用程序提供）：此修订的赠款应用的重点是内源气态生物介体硫化物（H2S）在大肠癌中的作用。基于多种新数据，我们开发了一种新的假设，即胱淀粉 - 伴侣酶（CBS）的选择性上调以及随后在结肠癌细胞中H2S的产生，通过刺激肿瘤细胞生物能力，生长，增殖，繁殖，移民和入侵来刺激肿瘤细胞生物能力，可作为促寿命因子。为了探索这个概念，我们将追求以下目的：＃1。为了表征CBS/H2S轴促进肿瘤细胞生物能和肿瘤细胞增殖的分子机制；＃2。确定CBS/H2S轴促进肿瘤细胞迁移，侵袭和转移的分子机制；和＃3。为了评估CBS抑制剂氨基乙酸（AOAA）对人结直肠癌的影响，在使用患者衍生的异种移植物（PDTX）与当前临床抗癌药物结合使用的转换相关动物模型中。综上所述，当前的项目将利用人类结肠癌组织，人类结肠癌细胞系和经过异位型人类结肠癌系或患者衍生的异种移植物进行异位移植的肿瘤小鼠。为了解决CBS的作用，将使用遗传（CBS沉默）和药物（CBS抑制剂）方法的组合。 Outcome variables will include parameters of bioenergetics (oxidative phosphorylation, mitochondrial electron transport, glycolysis, GAPDH activity), cell proliferation, cell growth (including activation of pr-inflammatory/pro-growth kinase pathways), tumor cell migration, tumor cell invasion, angiogenesis and metastasis in vitro and in vivo.还将在相关蛋白靶标（GAPDH，PTEN，PI3K）上探索硫化（特定的H2S介导的翻译后蛋白质修饰）的作用。最终翻译的目标将通过测试CBS抑制剂的抗癌作用来包含对潜在治疗相关性的研究，总而言之，当前的项目实体一种全面的方法来测试CBS/H2S的重要性，是结直肠癌中新型途径的重要性，并融入了早期翻译工作，以探索其潜在的抗抗癌目标。