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（由适用提供）：癌症引起的恶病质（癌症恶病质）是一种浪费综合征，其肌肉质量逐渐丧失（肌肉浪费）很大程度上是由于蛋白水解过量而导致的。在所有癌症患者中，痛苦约50％，癌症恶病质是所有与癌症相关的死亡中约1/3的直接原因。但是，由于对病因的了解不足，因此没有FDA批准的癌症恶病质治疗方法。癌症患者的标志是肌原纤维蛋白的急剧丧失。泛素 - 蛋白酶体途径在各种形式的肌肉萎缩中丧失的肌原纤维蛋白损失中起着重要作用，该途径通过靶向肌原纤维蛋白来通过特定的E3泛素连接酶降解。目前，人们普遍认为，癌症引起的肌肉浪费与其他类型的肌肉萎缩共享常见的细胞内机制。例如，E3连接酶MURF1升高被认为是包括癌症恶病质在内的所有形式的肌肉萎缩的中心。另外，认为Akt-FoxO1/3信号通路对于所有形式的肌肉萎缩至关重要，因为它调节了MURF1的表达。然而，最近的数据表明，癌症引起的肌肉浪费似乎涉及独特的细胞内机制，这些机制与诸如禁食，废弃或神经膜等身体压力引起的肌肉萎缩不同。新兴的证据表明，MURF1上调和Akt-FoxO1/3信号传导途径对于动物模型和人类患者的癌症引起的肌肉浪费是非必需的。取而代之的是，我们发现涉及转录因子C/EBPß激活p38 MAPK激活的注射激活的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。相比之下，MURF1和FOXO1/3对此模型中的肌肉浪费概不负责。此外，我们发现c/ebpß上调了先前被忽略的E3 UBR2，以响应肿瘤灼伤。 UBR2是E3连接酶家族的成员，它是N端规则途径的底物识别成分，该途径是总蛋白质泛素化的很大一部分，并且由各种分解代谢刺激诱导的肌肉蛋白质依赖于ATP依赖性降解。在这个E3家族中，UBR2在含肿瘤啮齿动物的肌肉中唯一更新。因此，我们建议检验以下假设：UBR2是癌症恶病质中肌原纤维蛋白过剩的关键E3，并通过阐明详细的信号机制来介导UBR2上调癌症cachexia中UBR的详细信号传导机制，我们可以通过使用现有的Pharmace insace intakiential Indibitors来降低肌肉浪费，从而降低肌肉浪费，从而降低肌肉浪费。目的1。确定UBR2是否是负责癌症引起的肌肉浪费并识别其底物的关键E3泛素连接酶。目标2。确定C/EBPß的位点特异性乙酰化是否介导了癌症诱导的C/EBPß的乙酰化。目标3。确定介导癌症诱导的C/EBPß乙酰化的信号传导机制。