Regulation of TRAIL Induced Apoptosis in Cancer Cells

TRAIL 诱导癌细胞凋亡的调节

• 批准号: 8236931
• 负责人: Gary Thomas
• 金额: $ 18.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236931
• 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because understanding precisely how cancer cells become resistant to TRAIL therapy and how this knowledge can lead, in turn, to novel therapeutic interventions that restore TRAIL-sensitivity is crucial for maximizing the potential of this promising cancer therapeutic. Thus, the proposed research is relevant to the part of NIH's mission supporting fundamental research that will ultimately cure disease.

描述（由申请人提供）：TNF超家族死亡配体TRAIL基于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途的癌症治疗剂的潜力至关重要。长期目标是准确了解癌细胞如何对TRAIL治疗产生耐药性，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。本申请的目的是确定TRAIL如何通过将多功能分选蛋白PACS-2转换为凋亡效应物来杀死癌细胞，以及PACS-2的失调如何使癌症能够抵抗TRAIL诱导的细胞死亡。具体而言，Akt-磷酸化PACS-2通过协调抗凋亡钙通道定位于内质网（ER）与ER-线粒体通讯来介导健康细胞中的稳态。响应于TRAIL，PACS-2变得去磷酸化，通过协调凋亡钙信号传导与介导Bid活化的溶酶体-线粒体通信来促进线粒体透化和细胞死亡。中心假设是PACS-2的失调使得癌细胞能够以两种不同的方式抵抗TRAIL杀伤：在具有升高的Akt的癌症中，PACS-2凋亡活性被持续的Akt磷酸化抑制，而在具有PACS-2基因座缺失的癌症中，TRAIL诱导的凋亡被抑制而不依赖于Akt状态。拟议研究的基本原理是，成功完成将建立PACS-2失调和肿瘤进展之间的因果关系，并将确定TRAIL如何将PACS-2转换为凋亡介体，协调线粒体透化和癌细胞死亡所需的复杂细胞器间通讯。在强有力的初步数据的指导下，将通过追求三个具体目标来检验艾德的假设：1）确定PACS-2的丢失或抑制在多大程度上加速肿瘤进展，2）鉴定TRAIL用于诱导PACS-2的凋亡活化以介导ER-线粒体钙信号传导的机制，和3）确定TRAIL如何诱导PACS-2协调溶酶体膜透化与线粒体上组织蛋白酶B介导的Bid切割。该方法是创新的，因为它使用了一个全面的，多学科的设计来剖析TRAIL作用的分子基础。这项研究意义重大，因为它提出了一种新的可测试模型，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在一起，因此PACS-2失调如何加速肿瘤进展并导致对TRAIL治疗的耐药性。 公共卫生相关性：拟议的研究与公共卫生有关，因为准确了解癌细胞如何对TRAIL治疗产生耐药性，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，对于最大限度地发挥这种有前途的癌症治疗的潜力至关重要。因此，拟议中的研究与NIH支持最终治愈疾病的基础研究的使命有关。