p53-mediated metabolic regulation in tumor suppression

p53介导的肿瘤抑制代谢调节

• 批准号: 10474447
• 负责人: Wei Gu
• 金额: $ 95.26万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474447
• 关键词: Apoptosis; Cell Cycle Arrest; Cell physiology; Development; Dissection; Event; Goals; Human; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Normal Cell; Normal tissue morphology; Pathway interactions; Regulation; Research; Role; TP53 gene; Tissue Therapy; Toxic effect; Tumor Suppression; base; cancer cell; cancer therapy; in vivo; novel; programs; senescence; transcription factor; tumor; tumor growth

Project Summary Inactivation of the p53 tumor suppressor is a pivotal event in the formation of most human cancers. p53 acts as a transcription factor to modulate various types of cellular processes to suppress cancer development. Although the classic activities of p53 including cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, accumulating evidence suggests that other unconventional mechanisms such as metabolic regulation are also critically involved in suppressing tumor growth. Nevertheless, despite the fact that the role of the p53 pathway in tumor suppression is indisputable, it remains a daunting task how to target this pathway for cancer therapy. The main issue is whether activation of p53 function in vivo leads to significant tumor regression without causing serious toxicity in normal tissues. Cancer cells rewire cellular metabolism to meet the energetic and substrate demands of tumor development, but this rewiring also creates metabolic vulnerabilities specific for cancer cells. By taking advantage of these metabolic vulnerabilities, our preliminary studies showed that specific activation of the tumor suppression function of p53 through certain metabolic targets can be effective in suppressing tumor growth but apparently does not cause severe harm to normal tissues. The central objective of the proposed research plan is to comprehensively define p53-mediated metabolic regulation program that is required for its tumor suppression as a mean to identify new targets/pathways for therapy. Toward this end, our research program will be based on two complementary lines of research aiming to the further dissection of: 1) p53-mediated metabolic pathways required for its tumor suppression; 2) the novel ferroptosis pathway regulated by p53 and the effects in both normal and cancer cells. We expect that the research program described above will identify specific targets to suppress tumor growth but have minimal or at least manageable toxicity in normal tissues.

项目摘要 p53肿瘤抑制剂的失活是大多数人形成的关键事件 癌症。 p53充当转录因子，以调节各种类型的细胞过程 抑制癌症发展。尽管p53的经典活动在内，包括细胞周期逮捕，但 衰老和凋亡是癌症发展的关键障碍，积累 有证据表明，其他非常规机制（例如代谢调节）也是 严重参与抑制肿瘤生长。然而，尽管事实是 肿瘤抑制中的p53途径是无可争议的，它仍然是一项艰巨的任务。 癌症治疗的途径。主要问题是p53在体内功能的激活是否导致 显着的肿瘤消退，而不会引起正常组织中的严重毒性。癌细胞重新布线 细胞代谢以满足肿瘤发育的能量和底物需求，但这 重新布线还产生了针对癌细胞特有的代谢脆弱性。通过利用 这些代谢脆弱性，我们的初步研究表明肿瘤的特异性激活 p53通过某些代谢靶标的抑制功能可以有效抑制 肿瘤生长，但显然不会对正常组织造成严重伤害。中央 拟议的研究计划的目的是全面定义p53介导的代谢 抑制肿瘤所必需的法规计划是识别新的 治疗的目标/途径。为此，我们的研究计划将基于两个 旨在进一步解剖的互补研究线：1）P53介导的代谢 肿瘤抑制所需的途径； 2）由p53调节的新型铁凋亡途径 以及正常和癌细胞的影响。我们希望研究计划描述 以上将确定抑制肿瘤生长的特定靶标，但至少具有最小 正常组织中的可管理毒性。