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（由申请人提供）：本修订后的拨款申请重点关注内源性气态生物介质硫化氢 (H2S) 在结直肠癌中的作用。基于多条新数据，我们提出了选择性上调胱硫醚的新假设。 ¿ -合酶（CBS）和随后在结肠癌细胞中产生的 H2S 通过刺激肿瘤细胞生物能、生长、增殖、迁移和侵袭来充当促生存因子。以下目标： #1. 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。 #3. 在利用患者来源的异种移植物 (PDTX) 结合当前临床的转化相关动物模型中评估 CBS 抑制剂氨基氧乙酸 (AOAA) 对人类结直肠癌的作用总而言之，当前的项目将利用人类结肠癌组织、人类结肠癌细胞系和接受人类结肠癌细胞系异位移植或患者来源的异种移植物的荷瘤小鼠来解决 CBS 的作用。将使用遗传（CBS 沉默）和药理学（CBS 抑制剂）方法的组合，结果变量将包括生物能学参数（氧化磷酸化、线粒体电子传递、糖酵解、GAPDH）。活性）、细胞增殖、细胞生长（包括促炎/促生长激酶途径的激活）、肿瘤细胞迁移、肿瘤细胞侵袭、体外和体内血管生成和转移（一种特定的 H2S 介导的作用）。翻译后蛋白质修饰）也将在相关蛋白质靶标（GAPDH、PTEN、PI3K）上进行探索，最终的转化目标将包括通过测试 CBS 抑制剂的抗癌作用来研究潜在的治疗相关性。当前的项目需要采用一种综合方法来测试 CBS/H2S 这一新途径在结直肠癌中的重要性，并结合早期转化工作来探索其作为抗癌治疗靶点的潜在效用。