Integrins and Caspase 8 in Tumor Progression

整合素和 Caspase 8 在肿瘤进展中的作用

• 批准号: 7985022
• 负责人: Dwayne G Stupack
• 金额: $ 30.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/7985022
• 关键词: Adhesions; Adult; Antigen Receptors; Apoptosis; Apoptotic; Binding; Biochemical; Birds; Blood Vessels; Carcinoma; Caspase; Catalytic Domain; Cell Adhesion; Cell Survival; 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; public health relevance; receptor; therapy design; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The protein "caspase 8" is well known to be involved in programmed cell death, and its expression is suppressed among aggressive neuroendocrine tumors. However, caspase 8 can also promote cell migration, and we show that it actually enhances the spread of death-resisting cells, which may explain why it is frequently upregulated in carcinoma. This proposal seeks to understand the molecular mechanisms that control caspase 8 switching between these two roles.

描述（由申请人提供）：在之前的资助期间，我们证明了caspase 8与未连接的整合素在体内的结合促进了细胞凋亡，并且神经母细胞瘤中caspase 8或整合素的下调促进了肿瘤转移。 在这些研究中，我们发现了一个矛盾的观察结果，即在抗凋亡细胞中，caspase 8的表达显著增强了整合素介导的体外迁移和体内转移。 因此，本提案的总体目标是了解caspase 8凋亡与非凋亡功能是如何调节的。 caspase 8作为caspase的启动子，在死亡受体、toll样受体和整合素下游触发细胞凋亡。 其表达在侵袭性神经母细胞瘤和其他神经内分泌肿瘤中经常丢失。 这促使临床策略寻求恢复或扩增其表达。 然而，胱天蛋白酶8不足以用于凋亡，而是需要顺应性下游胱天蛋白酶级联。 在肿瘤转移受损的细胞中，我们提供了caspase 8表达实际上增强肿瘤转移的证据。 这一令人惊讶的结果值得重新考虑的概念，简单的上调半胱天冬酶8是普遍有益的;相反，它可能会加剧疾病的进展。 虽然免疫和血管隔室中的胱天蛋白酶8的非凋亡功能是已知的，但使胱天蛋白酶8发挥这些功能的机制尚不清楚。 在这里，我们提供的初步结果表明，增强细胞迁移发生的同时，半胱天冬酶8酪氨酸磷酸化和定位在粘着斑接触后整合素连接。 该提案的目的1将表征在粘附过程中磷酸化的特定半胱天冬酶8酪氨酸残基，并确定那些对迁移至关重要的残基。 目的2将评估哪些酪氨酸残基影响半胱天冬酶8的催化和促凋亡活性，包括蛋白质-蛋白质相互作用。 最后，AIM 3将测试这些调节性酪氨酸残基对体内疾病进展的影响。 总之，这些研究的结果将揭示caspase 8调节的分子机制，这对抗转移疗法的发展至关重要。 公共卫生关系：众所周知，蛋白质"半胱天冬酶8"参与程序性细胞死亡，并且其表达在侵袭性神经内分泌肿瘤中受到抑制。 然而，半胱天冬酶8也可以促进细胞迁移，我们发现它实际上增强了抗死亡细胞的扩散，这可以解释为什么它在癌症中频繁上调。 该提案旨在了解控制caspase 8在这两个角色之间切换的分子机制。