Regulation of TRAIL Induced Apoptosis in Cancer Cells

TRAIL 诱导癌细胞凋亡的调节

• 批准号: 8620615
• 负责人: Gary Thomas
• 金额: $ 30.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-04 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620615
• 关键词: Apoptosis; Apoptotic; Binding; Biochemical; CCL4 gene; Calcium; Calcium Channel; Calcium Signaling; Cathepsins B; Cell Death; Cells; Cellular biology; Cessation of life; Colorectal; Communication; Complex; Data; Disease; Endoplasmic Reticulum; Gene Deletion; Goals; Homeostasis; Human; Ion Channel; Knowledge; Lead; Ligands; Lysosomes; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Mission; Mitochondria; Modeling; Molecular; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Phosphorylation; Process; Prostate; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Public Health; Recurrence; Regulation; Repression; Research; Resistance; Role; Signal Transduction; Solid Neoplasm; Sorting - Cell Movement; Staging; TNFSF10 gene; Testing; Therapeutic; Tumor Cell Line; Tumor Necrosis Factor-alpha; Work; base; cancer cell; design; fundamental research; in vivo; innovation; killings; lysosome membrane; malignant breast neoplasm; mouse model; novel; novel therapeutic intervention; prevent; public health relevance; response; tool; trafficking; tumor; tumor progression

DESCRIPTION (provided by applicant): The TNF superfamily death ligand TRAIL is emerging as a potential tool in the treatment of many cancers based on its ability to selectively kill cancer cells and repress tumor metastasis. Unfortunately, many tumor cell lines are resistant to TRAIL, suggesting the molecular basis of TRAIL action and how TRAIL-sensitivity can be restored is crucial for maximizing the potential of this promising cancer therapeutic. The long-term goal is to understand precisely how cancer cells become resistant to TRAIL therapy and how this knowledge can, in turn, lead to novel therapeutic interventions that restore TRAIL-sensitivity. The objective in this particular application is to determine how TRAIL kills cancer cells by switching the multifunctional sorting protein PACS-2 to an apoptotic effector and how dysregulation of PACS-2 enables cancers to resist TRAIL-induced cell death. Specifically, Akt-phosphorylated PACS-2 mediates homeostasis in healthy cells by coordinating the localization of antiapoptotic calcium channels to the endoplasmic reticulum (ER) with ER-mitochondria communication. In response to TRAIL, PACS-2 becomes dephosphorylated, promoting mitochondria permeabilization and cell death by coordinating apoptotic calcium signaling with lysosome-mitochondria communication that mediates Bid activation. The central hypothesis is that dysregulation of PACS-2 enables cancer cells to resist TRAIL killing in two different ways: in cancers with elevated Akt, PACS-2 apoptotic activity is repressed by persistent Akt phosphorylation, whereas in cancers with loss of the PACS-2 locus, TRAIL-induced apoptosis is repressed independent of Akt status. The rationale for the proposed research is that successful completion will establish a causal relationship between PACS-2 dysregulation and tumor progression and will determine how TRAIL switches PACS-2 to an apoptotic mediator that coordinates the complex interorganellar communication required for mitochondria permeabilization and cancer cell death. Guided by strong preliminary data, this hypothesis will be test- ed by pursuing three specific aims: 1) Determine to what extent loss or repression of PACS-2 accelerates tumor progression, 2) Identify the mechanism used by TRAIL to induce apoptotic activation of PACS-2 to mediate ER-mitochondria calcium signaling, and 3) Determine how TRAIL induces PACS-2 to coordinate lysosome membrane permeabilization with cathepsin B-mediated Bid cleavage on mitochondria. The approach is innovative because it uses a comprehensive, multi-disciplinary design to dissect the molecular basis of TRAIL action. The proposed research is significant because it presents a novel and testable model of how PACS-2 acts as a molecular switch to integrate cell homeostasis with TRAIL-induced apoptosis and, therefore, how PACS-2 dysregulation may accelerate tumor progression and cause resistance to TRAIL therapy.

描述（由申请人提供）：TNF超家族死亡配体TRAIL因其选择性杀死癌细胞和抑制肿瘤转移的能力而成为治疗许多癌症的潜在工具。不幸的是，许多肿瘤细胞系对 TRAIL 具有抗性，这表明 TRAIL 作用的分子基础以及如何恢复 TRAIL 敏感性对于最大限度地发挥这种有前景的癌症治疗药物的潜力至关重要。长期目标是准确了解癌细胞如何对 TRAIL 疗法产生耐药性，以及这些知识如何反过来导致恢复 TRAIL 敏感性的新型治疗干预措施。这一特定应用的目的是确定 TRAIL 如何通过将多功能分选蛋白 PACS-2 转变为凋亡效应子来杀死癌细胞，以及 PACS-2 的失调如何使癌症能够抵抗 TRAIL 诱导的细胞死亡。具体来说，Akt 磷酸化的 PACS-2 通过协调抗凋亡钙通道在内质网 (ER) 的定位与 ER-线粒体通讯来介导健康细胞的稳态。响应 TRAIL，PACS-2 变得去磷酸化，通过协调凋亡钙信号传导与介导 Bid 激活的溶酶体-线粒体通讯来促进线粒体透化和细胞死亡。核心假设是，PACS-2 的失调使癌细胞能够以两种不同的方式抵抗 TRAIL 杀伤：在 Akt 升高的癌症中，PACS-2 凋亡活性受到持续 Akt 磷酸化的抑制，而在 PACS-2 缺失的癌症中位点，TRAIL 诱导的细胞凋亡受到抑制，与 Akt 状态无关。拟议研究的基本原理是，成功完成将建立 PACS-2 失调与肿瘤进展之间的因果关系，并将确定 TRAIL 如何将 PACS-2 转变为细胞凋亡介质，协调线粒体透化和癌细胞死亡所需的复杂细胞间通讯。在强有力的初步数据的指导下，这一假设将通过三个具体目标进行检验：1) 确定 PACS-2 的缺失或抑制在多大程度上加速肿瘤进展，2) 确定 TRAIL 用于诱导 PACS 凋亡激活的机制-2 介导 ER-线粒体钙信号传导，以及 3) 确定 TRAIL 如何诱导 PACS-2 与组织蛋白酶 B 介导的 Bid 协调溶酶体膜透化线粒体上的裂解。该方法具有创新性，因为它采用全面的多学科设计来剖析 TRAIL 作用的分子基础。拟议的研究具有重要意义，因为它提出了一种新颖且可测试的模型，说明 PACS-2 如何作为分子开关将细胞稳态与 TRAIL 诱导的细胞凋亡整合起来，以及 PACS-2 失调如何加速肿瘤进展并导致对 TRAIL 的耐药性治疗。