p53-mediated metabolic regulation in tumor suppression

项目摘要 p53肿瘤抑制因子的失活是大多数人类肿瘤形成中的关键事件。 癌的p53作为转录因子调节各种类型的细胞过程， 抑制癌症发展。尽管p53的经典活性包括细胞周期阻滞， 衰老和凋亡是癌症发展的关键障碍， 有证据表明，其他非常规机制，如代谢调节，也是 在抑制肿瘤生长中起着关键作用。然而，尽管事实上， p53通路在肿瘤抑制中的作用是无可争议的，如何靶向这一点仍然是一项艰巨的任务 癌症治疗的途径。主要的问题是体内p53功能的激活是否会导致 显著的肿瘤消退，而不会在正常组织中引起严重的毒性。癌细胞重新连接 细胞代谢，以满足肿瘤发展的能量和底物需求，但这 重新连接也会造成癌细胞特有的代谢脆弱性。通过利用 我们的初步研究表明，肿瘤的特异性激活 p53通过某些代谢靶点的抑制功能可以有效地抑制 肿瘤生长，但显然不会对正常组织造成严重伤害。中央 该研究计划的目的是全面定义p53介导的代谢 调节程序，其肿瘤抑制所需的手段，以确定新的 治疗的目标/途径。为此，我们的研究计划将基于两个 补充线的研究，旨在进一步解剖：1）p53介导的代谢 p53调控的新型铁凋亡途径 以及对正常细胞和癌细胞的影响。我们希望研究计划所描述的 以上将鉴定抑制肿瘤生长的特异性靶点，但具有最小或至少 在正常组织中可控制的毒性。

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.