Intramuscular Mechanisms of Cancer Cachexia

癌症恶病质的肌内机制

基本信息

批准号：
8973067
负责人：
YI-PING LI
金额：
$ 45.78万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8973067
关键词：
Accounting Acetylation Affinity Animal Model Animals Binding Biological Assay Cachexia Cancer Etiology Cancer Intervention Cancer Patient Cessation of life Clinical Clinical Trials DNA Data Denervation Development Dominant-Negative Mutation EP300 gene Etiology FDA approved Family Fasting Future Genes Genetic Genetic Transcription Human In Vitro Inflammation Intramuscular Investigational Therapies Knock-out MAP Kinase Gene MAPK14 gene Malignant Neoplasms Malignant neoplasm of lung Maps Mediating Modeling Molecular Mus Muscle Muscle Cells Muscle Fibers Muscle Proteins Muscular Atrophy Mutate Myomatous neoplasm Pathway interactions Patients Phosphorylation Phosphorylation Site Physiological Play Post-Translational Protein Processing Proteins Proteolysis Proteomics Rodent Role Signal Pathway Signal Transduction Site Stimulus Stress Testing Therapeutic Transactivation Transcription Factor 3 Tumor Burden Ubiquitin Up-Regulation Wasting Syndrome cancer cachexia cancer therapy design drug development factor C in vivo inhibitor/antagonist kinase inhibitor knock-down loss of function member multicatalytic endopeptidase complex muscle form mutant protein degradation public health relevance response therapeutic target transcription factor tumor ubiquitin-protein ligase wasting

项目摘要

DESCRIPTION (provided by applicant): Cancer-induced cachexia (cancer cachexia) is a wasting syndrome featuring progressive loss of muscle mass (muscle wasting) due largely to excessive proteolysis. Afflicting ~50% of all cancer patients, cancer cachexia is the immediate cause of ~1/3 of all cancer-related deaths. However, there is no FDA-approved treatment for cancer cachexia due to the poor understanding of its etiology. A hallmark of cancer cachexia is the dramatic loss of myofibrillar proteins. The ubiquitin-proteasome pathway plays a major role in the loss of myofibrillar proteins in various forms of muscle atrophy by targeting myofibrillar proteins for degradation via specific E3 ubiquitin ligases. Currently, cancer-induced muscle wasting is widely thought to share common intracellular mechanisms with other types of muscle atrophy. For example, elevated E3 ligase MuRF1 is considered central for ALL forms of muscle atrophy including cancer cachexia. In addition, the Akt-FoxO1/3 signaling pathway is thought critical for ALL forms of muscle atrophy because it regulates MuRF1 expression. However, recent data revealed that cancer-induced muscle wasting appears to involve unique intracellular mechanisms distinct from muscle atrophy induced by physiological stress such as fasting, disuse or denervation. Emerging evidence suggests that MuRF1 upregulation and the Akt-FoxO1/3 signaling pathway are non-essential for cancer-induced muscle wasting in animal models as well as human patients. Instead, we found that an inflammation-activated signaling pathway involving p38 MAPK activation of transcription factor C/EBPß is responsible for the bulk of muscle protein degradation in a mouse cancer cachexia model. In contrast, MuRF1 and FoxO1/3 are not responsible for the muscle wasting in this model. Further, we found that C/EBPß upregulates a previously overlooked E3, UBR2, in response to a tumor burden. UBR2 is a member of an E3 ligase family that serves as the substrate recognition components of the N-end rule pathway that accounts for a large portion of total protein ubiquitylation and ATP-dependent degradation of muscle proteins induced by various catabolic stimuli. Within this E3 family, UBR2 is uniquely upregulated in the muscle of tumor-bearing rodents. Thus, we propose to test the hypothesis that UBR2 is a key E3 responsible for the excessive loss of myofibrillar proteins in cancer cachexia, and by elucidating detailed signaling mechanisms that mediate UBR2 upregulation in cancer cachexia we can ameliorate muscle wasting by targeting the signaling mechanisms using existing pharmacological inhibitors through pursuing three aims. Aim 1. To determine whether UBR2 is a key E3 ubiquitin ligase responsible for cancer-induced muscle wasting and identify its substrates. Aim 2. To determine whether site-specific acetylation of C/EBPß mediates cancer-induced UBR2 upregulation. Aim 3. To determine the signaling mechanism that mediates cancer-induced acetylation of C/EBPß.

描述（由申请人提供）：癌症引起的恶病质（癌症恶病质）是一种消耗综合征，其特征是主要由于过度蛋白水解而导致肌肉质量进行性损失（肌肉消耗）。约 50% 的癌症患者患有癌症恶病质，这是其直接原因。约 1/3 的癌症相关死亡。然而，由于对癌症恶病质的病因了解甚少，因此尚无 FDA 批准的治疗方法。泛素蛋白酶体途径在各种形式的肌肉萎缩中通过特异性 E3 泛素连接酶降解肌原纤维蛋白，在肌原纤维蛋白的丧失中发挥着重要作用。目前，癌症引起的肌肉萎缩广泛存在。人们认为与其他类型的肌肉萎缩具有共同的细胞内机制，例如，E3 连接酶 MuRF1 升高被认为是所有形式的肌肉萎缩的核心，包括。此外，Akt-FoxO1/3 信号通路被认为对所有形式的肌肉萎缩都至关重要，因为它调节 MuRF1 的表达。然而，最近的数据表明，癌症引起的肌肉萎缩似乎涉及与肌肉萎缩不同的独特细胞内机制。禁食、废用或去神经支配等生理应激引起的新证据表明，MuRF1 上调和 Akt-FoxO1/3 信号通路对于癌症引起的动物肌肉萎缩并不是必需的。相反，我们发现涉及转录因子 C/EBPß 的 p38 MAPK 激活的炎症激活信号通路是小鼠癌症恶病质模型中大部分肌肉蛋白降解的原因。 /3 不导致该模型中的肌肉萎缩。此外，我们发现 C/EBPß 上调先前被忽视的 E3，UBR2，以响应肿瘤负荷。 E3 连接酶家族，作为 N 端规则途径的底物识别组件，占总蛋白泛素化和各种分解代谢刺激诱导的肌肉蛋白 ATP 依赖性降解的很大一部分。在该 E3 家族中，UBR2 独特地上调。因此，我们建议检验 UBR2 是导致癌症恶病质中肌原纤维蛋白过度丢失的关键 E3 的假设，并详细阐明。介导癌症恶病质中 UBR2 上调的信号机制我们可以通过使用现有的药物抑制剂靶向信号机制来改善肌肉萎缩，目标 1. 确定 UBR2 是否是导致癌症诱导肌肉萎缩的关键 E3 泛素连接酶并确定。目标 2. 确定 C/EBPß 的位点特异性乙酰化是否介导癌症诱导的 UBR2 上调。介导癌症诱导的 C/EBPß 乙酰化的信号机制。