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Integrins and Caspase 8 in Tumor Progression

整合素和 Caspase 8 在肿瘤进展中的作用

基本信息

批准号：
8665527
负责人：
Dwayne G Stupack
金额：
$ 6.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-06 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8665527
关键词：
Adhesions Adult Antigen Receptors Apoptosis Apoptotic Binding Biochemical Birds Blood Vessels Carcinoma Caspase Catalytic Domain Cell Survival Cell-Cell Adhesion Cells Cessation of life Child Clinical Clinical Trials Commit Complement Complex Development Disease Progression Down-Regulation Epithelial Exhibits Extracellular Matrix Extracellular Matrix Proteins Focal Adhesions Funding Genes Genetic Goals Homologous Gene Human Immune In Vitro Integrins Ligation Link Malignant Neoplasms Mammals Maps Mass Spectrum Analysis Mediating Methylation Molecular Mus Neoplasm Metastasis Neuroblastoma Neuroendocrine Tumors Pathway interactions Phosphorylation Phosphorylation Site Play Pre-Clinical Model Proteins Regulation Resistance Risk Role Signal Transduction Site Solid Neoplasm Solvents Testing Toll-like receptors Tyrosine Tyrosine Phosphorylation Up-Regulation caspase-10 caspase-8 cell motility gene function in vivo migration oncology prevent protein protein interaction receptor therapy design tumor tumor growth tumor progression

项目摘要

Caspase 8 and Integrins in Tumor Progression During the previous funding period, we demonstrated that caspase 8 association with unligated integrins in vivo promoted apoptosis, and that down-regulation of caspase 8 or integrins in neuroblastoma promoted tumor metastasis. Confirming the roll of apoptosis in these studies, we made the paradoxical observation that, among apoptosis-resistant cells, the expression of caspase 8 significantly enhanced integrin-mediated migration in vitro and metastasis in vivo. The overall goal of this proposal is therefore to understand how caspase 8 apoptotic vs nonapoptotic function is regulated. As an initiator caspase, caspase 8 triggers apoptosis downstream of death receptors, toll-like receptors and integrins. Its expression is frequently lost among aggressive neuroblastoma and other neuroendocrine tumors. This has prompted clinical strategies seeking to restore or amplify its expression. However, caspase 8 is not sufficient for apoptosis, but requires a compliant downstream caspase cascade. Among apoptosis-compromised cells, we provide evidence that caspase 8 expression actually functions to enhance tumor metastasis. This surprising result warrants reconsideration of the concept that simple upregulation of caspase 8 is universally beneficial; rather, it may exacerbate disease progression. While nonapoptotic functions of caspase 8 within the immune and vascular compartments are known, the mechanisms committing caspase 8 to these functions are not. Here, we provide preliminary results showing that enhanced cell migration occurs concurrent with caspase 8 tyrosine phosphorylation and localization in focal adhesion contacts following integrin ligation. AIM 1 of this proposal will characterize the specific caspase 8 tyrosine residues phosphorylated during adhesion, and identify those critical for migration. AIM 2 will evaluate which tyrosine residues influence caspase 8 catalytic and proapoptotic activities, including protein-protein interactions. Finally, AIM 3 will test the impact of these regulatory tyrosine residues on disease progression in vivo. Together, the results of these studies will reveal molecular mechanisms of caspase 8 regulation important for the development of anti-metastatic therapies.

Caspase 8和整合素在肿瘤进展中的作用