p53-mediated metabolic regulation in tumor suppression

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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.