Pdcd4-Rictor Interaction in Suppression of Lung Tumorigenesis

Pdcd4-Rictor 相互作用抑制肺肿瘤发生

• 批准号: 10798949
• 负责人: Hsin-Sheng Yang
• 金额: $ 49.11万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798949
• 关键词: 6-Phosphofructo-2-kinase; Acetylation; Apoptosis; Binding; Biological; Biological Assay; Cancer Etiology; Cancer Patient; Cause of Death; Cell Proliferation; Cell Survival; Cells; Cessation of life; Companions; Complex; Cultured Cells; Data; Drug Kinetics; Early Diagnosis; Event; Exhibits; FRAP1 gene; Feedback; Fructose; Gene Amplification; Genes; Genetic; Genetic Transcription; Glycolysis; Growth; In Vitro; Inhibition of Cell Proliferation; Invaded; Investigation; Knock-out; Laboratories; Malignant neoplasm of lung; Maps; Mediating; Metabolic Pathway; Mutation; Mutation Analysis; Neoplasm Metastasis; New Agents; Non-Small-Cell Lung Carcinoma; Nude Mice; Outcome Study; Patients; Penetration; Peptides; Phosphorylation; Phosphorylation Site; Phosphotransferases; Process; Prognosis; Proliferating; Proteasome Inhibitor; Proteins; Regulation; Reporting; Resistance; Role; Signal Transduction; Sirolimus; Site; Subgroup; Survival Rate; Tertiary Protein Structure; Testing; Therapeutic; Tumor Suppressor Proteins; Ubiquitination; United States; Up-Regulation; Woman; Work; Xenograft procedure; cancer cell; cancer diagnosis; cancer type; improved; in vivo; inhibitor; knock-down; lung cancer cell; lung tumorigenesis; men; metabolomics; migration; mortality; multicatalytic endopeptidase complex; mutant; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; precision medicine; prevent; research clinical testing; response; small cell lung carcinoma; therapy resistant; tumor; tumor growth; tumorigenesis; ubiquitin-protein ligase

Project Summary/Abstract Lung cancer is the leading cause of cancer-related deaths in the United States. The high mortality rate is not only due to the lack of effective early detection but also due to poor tumor response to currently available therapies. These underscore the urgent need to better understand the biological events and mechanism of lung cancer suppression, as is the need for important new therapeutic approaches that specifically target these processes to improve survival rates. Lung cancer is mainly divided into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), the latter of which accounts for 80-85% of all cases. A new subset of lung cancer in both SCLC and NSCLC was recently identified in which Rapamycin-insensitive companion of mTOR (Rictor) gene is amplified. Rictor is an essential component of the mammalian target of rapamycin complex 2 (mTORC2) and is required for mTORC2 complex activity and integrity. Activation of mTORC2 results in promotion of cancer cell proliferation and survival. This application builds on exciting preliminary data that Programmed cell death 4 (Pdcd4) bound with Rictor through a Rictor binding domain (RBD) to inhibit mTORC2 activity, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) level, cell proliferation, and colony formation. In addition, a peptide containing the RBD specifically inhibits mTORC2 but not mTORC1. Our data further demonstrated that the RBD peptide suppressed NSCLC proliferation in cultured cells and nude mice. The central hypothesis is that Pdcd4-Rictor binding specifically inhibits mTORC2 to preferentially suppress proliferation in Rictor-elevated NSCLC via induction of proteasomal degradation of PFKFB3. To test this hypothesis, three specific aims are proposed: i) Delineate the mechanism of how Pdcd4-Rictor binding interferes with mTORC2 activity to suppress tumor growth in NSCLC; ii) Dissect how Pdcd4-Rictor-mTORC2 axis impacts PFKFB3 stability and metabolic pathways; iii) Demonstrate that mTORC2-specific inhibition by RBD peptide preferentially suppresses the growth of Rictor-elevated NSCLC to improve survival rate. The accomplishment of the proposed study will not only uncover novel regulatory mechanisms of mTORC2 activity and PFKFB3 expression by Pdcd4 but also reveal the importance of mTORC2-specific inhibition by RBD peptide on NSCLC tumorigenesis. The expected findings will guide us to develop new strategies that are particularly relevant to precision medicine approaches for NSCLC patients with elevated Rictor.

项目总结/摘要 肺癌是美国癌症相关死亡的主要原因。高死亡率并不是 这不仅是由于缺乏有效的早期检测，而且还由于肿瘤对目前可用的 治疗这些都强调迫切需要更好地了解肺的生物学事件和机制， 癌症抑制，因为需要重要的新的治疗方法，专门针对这些 以提高生存率。肺癌主要分为两种类型：小细胞肺癌（SCLC） 和非小细胞肺癌（NSCLC），后者占所有病例的80-85%。的新子集 最近发现小细胞肺癌和非小细胞肺癌中存在雷帕霉素不敏感的伴随物， 扩增mTOR（Rictor）基因。Rictor是雷帕霉素哺乳动物靶蛋白的重要组成部分 它是mTORC 2复合物的一部分，是mTORC 2复合物活性和完整性所必需的。mTORC 2激活结果 促进癌细胞增殖和存活。该应用程序基于令人兴奋的初步数据， 程序性细胞死亡4（Pdcd 4）通过Rictor结合结构域（RBD）与Rictor结合以抑制mTORC 2 活性、6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3）水平、细胞增殖和集落 阵此外，含有RBD的肽特异性抑制mTORC 2，但不抑制mTORC 1。我们的数据 进一步证明RBD肽抑制培养细胞和裸鼠中的NSCLC增殖。的 中心假设是Pdcd 4-Rictor结合特异性抑制mTORC 2优先抑制 通过诱导PFKFB 3的蛋白酶体降解在Rictor升高的NSCLC中增殖。为了验证这一 假设，提出了三个具体的目标：i）描述Pdcd 4-Rictor结合如何干扰的机制 ii）分析Pdcd 4-Rictor-mTORC 2轴如何影响 PFKFB 3稳定性和代谢途径; iii）证明RBD肽对mTORC 2的特异性抑制作用 优先抑制Rictor升高的NSCLC的生长以提高存活率。的完成 这项研究不仅将揭示mTORC 2活性和PFKFB 3的新的调节机制， Pdcd 4表达的抑制作用，而且还揭示了RBD肽对NSCLC的mTORC 2特异性抑制的重要性 肿瘤发生预期的研究结果将指导我们制定新的战略，特别是与以下方面有关的战略： Rictor升高的NSCLC患者的精确医学方法。