Integrins and Caspase 8 in Tumor Progression

Caspase 8和整合素在肿瘤进展中的作用 在上一个资助期，我们证明了半胱天冬酶8与未连接的 整合素在体内促进细胞凋亡，并下调半胱天冬酶8或整合素， 神经母细胞瘤促进肿瘤转移。为了说明这些研究中细胞凋亡的作用，我们 自相矛盾的观察结果是，在抗凋亡细胞中，caspase 8的表达 显著增强整合素介导的体外迁移和体内转移。的总目标 因此，该建议是为了了解caspase 8凋亡与非凋亡功能是如何调节的。 caspase 8作为一种启动子，在死亡受体Toll样受体下游触发细胞凋亡 和整联蛋白。它的表达在侵袭性神经母细胞瘤和其他神经母细胞瘤中经常丢失。 神经内分泌肿瘤这促使临床策略寻求恢复或扩大其 表情然而，半胱天冬酶8对于凋亡是不够的，而是需要一个顺应性的下游调节。 半胱天冬酶级联反应。在凋亡受损细胞中，我们提供了caspase 8 表达实际上起到增强肿瘤转移的作用。这一令人惊讶的结果证明， 重新考虑caspase 8的简单上调是普遍有益的概念;相反， 可能会加剧疾病进展。而caspase 8在免疫系统中的非凋亡功能， 和血管区室是已知的，使胱天蛋白酶8发挥这些功能的机制是 没有在这里，我们提供的初步结果表明，增强细胞迁移发生的同时， caspase 8酪氨酸磷酸化和定位在粘着斑接触后整合素 结扎本提案的目的1将表征特定的caspase 8酪氨酸残基 在粘附过程中磷酸化，并确定那些关键的迁移。AIM 2将评估哪些 酪氨酸残基影响caspase 8催化和促凋亡活性，包括蛋白质-蛋白质 交互.最后，AIM 3将测试这些调节性酪氨酸残基对疾病的影响 体内进展。总之，这些研究的结果将揭示 半胱天冬酶8调节对于抗转移疗法的发展是重要的。

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.