The Mechanism and Therapeutic Potential of Targeting the Ninjurin Pathway for Tumors Carrying Wild-Type p53

靶向 Ninjurin 通路治疗携带野生型 p53 的肿瘤的机制和治疗潜力

• 批准号: 10501882
• 负责人: Xinbin Chen
• 金额: $ 43.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501882
• 关键词: Amino Acid Sequence; Apoptosis; Biological; Biology; Breast Cancer Cell; Cell Adhesion Molecules; Cell Aging; Cell Cycle Arrest; Cell Death; Cessation of life; Chronic; Complex; DNA Damage; Data; Databases; Development; Embryo; Exposure to; Extracellular Domain; Family; Feedback; Fibroblasts; Genes; Genetic Translation; Genome; Growth; Health; Human; Hydrophobicity; Immune response; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; MCF7 cell; Malignant Neoplasms; Mus; Mutation; N-terminal; Neoplasm Metastasis; Nerve Regeneration; Neurons; Pathologic Processes; Pathway interactions; Peptides; Pilot Projects; Play; Proteins; Publishing; Regulation; Role; Schwann Cells; Signal Transduction; Spinal Ganglia; Stress; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Agents; Transmembrane Domain; Tumor Suppression; Up-Regulation; alpha helix; angiogenesis; cancer type; cell growth; cell motility; drug development; extracellular; neoplastic cell; nerve injury; novel; novel anticancer drug; overexpression; systemic inflammatory response; therapeutic target; transcription factor; tumor; tumor progression; tumorigenesis

Project Summary/Abstract The tumor suppressor p53 is often referred to as the “guardian of the genome”. Mutations of the p53 gene occur in ~50% of human cancer and loss of p53 function is known to play a central role in tumor progression and metastasis. Upon exposure to a stress signal, such as DNA damage, p53 transcription factor is activated and then induces an array of pro-survival and pro-death genes. Due to its potent role in tumor suppression, p53 is an attractive target for the development of new anticancer drugs. Nerve injury-induced protein 1 (Ninjurin1, NINJ1) and NINJ2 constitute the Ninjurin family of cell adhesion molecules and have been implicated in various pathological processes such as immune response. However, the role of NINJ1 and NINJ2 in tumorigenesis is unclear. We showed previously that NINJ1 is a target of p53 and in turn represses p53 mRNA translation. Thus, NINJ1 and p53 forms a negative feedback loop. Notably, our pilot study showed that NINJ1 and NINJ2 interact with each other through their N-terminal extracellular domains. We also found that like NINJ1, NINJ2 forms a negative regulatory loop with p53. To determine the biological significance of the NINJ1-NINJ2-p53 loop, we showed that: (1) loss of NINJ1 or NINJ2 inhibits cell migration and formation of tumor spheres and colonies in breast cancer cells and promote cellular senescence in mouse embryonic fibroblasts in a p53- dependent manner; (2) mice deficient in Ninj1 or Ninj2 are prone to chronic inflammation, which is likely due to enhanced pyroptosis through wild-type p53-dependent activation of NLRP3 inflammasome; (3) two small peptides, called Pep-1A and Pep-2A derived from N-terminal alpha helix domain of NINJ1 and NINJ2 protein were able to disrupt the formation of NINJ1-NINJ2 complex and elicit growth suppression. These observations prompt us to hypothesize that both NINJ1 and NINJ2 play a critical role in tumorigenesis through the p53 pathway. To test this, we will determine: (1) the feedback regulatory loops between NINJ1 and NINJ2 and between p53 and the Ninjurin family; (2) the biological significance of the NINJ1-NINJ2-p53 loop in tumor suppression; (3) whether the Ninj1- Ninj2-p53 loop can be targeted to kill tumor cells carrying wild-type p53.

项目摘要/摘要 肿瘤抑制p53通常被称为“基因组的监护人”。 p53的突变 〜50％的人类癌症的基因出现，p53功能的丧失在肿瘤中起着核心作用 进展和转移。暴露于应力信号（例如DNA损伤）后，p53转录 因子被激活，然后影响一系列亲卵巢和亲死亡基因。由于其强大的角色 在肿瘤抑制中，p53是开发新抗癌药物的有吸引力的靶标。神经 损伤诱导的蛋白1（NINJURIN1，NINJ1）和NINJ2构成细胞粘附的忍者家族 分子已在各种病理过程中隐含，例如免疫反应。 然而，忍者和忍者在肿瘤发生中的作用尚不清楚。我们以前证明了忍者 是p53的靶标，进而反映了p53 mRNA翻译。那，忍者和p53构成负面 反馈循环。值得注意的是，我们的试点研究表明，NINJ1和NINJ2通过 它们的N末端细胞外域。我们还发现，像忍者一样，ninj2形成负面 使用p53的调节循环。为了确定NINJ1-NINJ2-P53环的生物学意义，我们 结果表明：（1）否则NINJ1或NINJ2的损失抑制了细胞迁移和肿瘤球的形成和 乳腺癌细胞中的菌落并促进p53-中小鼠胚胎成纤维细胞中的细胞感应 依赖方式； （2）缺乏NINJ1或NINJ2的小鼠容易发生慢性炎症，这是 可能是由于NLRP3的野生型P53依赖性激活而增加的凋亡 炎症； （3）两个小肽，称为pep-1a和源自N末端α螺旋的PEP-2A NINJ1和NINJ2蛋白的结构域能够破坏NINJ1-NINJ2复合物的形成 引起生长抑制。这些观察结果促使我们假设NINJ1和NINJ2都 通过p53途径在肿瘤发生中起关键作用。为了测试这一点，我们将确定：（1） 忍者和忍者之间以及p53和忍者家族之间的反馈调节循环； （2） NINJ1-NINJ2-P53环路在肿瘤抑制中的生物学意义； （3）是否忍者 - NINJ2-P53环可以针对杀死带有野生型p53的肿瘤细胞。