Gain-of-function mutant p53 and metabolic reprogramming in colorectal cancer

抑癌基因P53在肿瘤预防中发挥着核心作用。在人类癌症中，p53经常发生突变， 包括结直肠癌(CRC)。许多突变型p53蛋白不仅失去对肿瘤的抑制作用 野生型P53的功能，也获得了新的致癌活性来促进肿瘤的发生，这被定义为 突变P53功能增益(GOF)。维持代谢动态平衡是P53的一个新的关键机制 肿瘤抑制。癌细胞经常表现出脂代谢重编程，这对 癌症进展。目前，突变P53在肿瘤代谢重编程中的作用和机制如下 定义不明确。我们的初步研究表明，突变的p53驱动脂代谢重新编程是一个关键 结直肠癌细胞中的GOF，靶向脂质代谢重编程折衷于结直肠癌中的muP53 GOF 肿瘤发生学。根据我们的初步结果，我们假设GOF突变P53驱动脂质代谢 重新编程是促进结直肠肿瘤发生的关键机制，可作为治疗的靶点 在携带突变P53的CRC中。在这项拟议的研究中，我们将确定的作用(目标1)和机制(目标2) Gof-mutp53在驱动结直肠癌脂代谢重编程中的作用。我们将进一步评估针对突变p53驱动的靶向 脂代谢重编程作为携带突变p53的结直肠癌的潜在治疗策略(目标3)。目标是 本研究旨在为确定GOF突变p53在结直肠癌中的作用机制提供有效的靶点和策略 接受结直肠癌治疗。代谢重新编程和p53突变是癌症中常见的事件，并有 成为癌症治疗的极具吸引力的靶点。我们期望这项拟议研究的结果 将加深我们对突变P53在代谢重编程中的作用和机制的理解 肿瘤的发生，并为开发新的治疗靶点和 携带突变P53的癌症的治疗策略。

Tumor suppressor p53 plays a central role in tumor prevention. p53 is frequently mutated in human cancer, including colorectal cancer (CRC). Many mutant p53 (mutp53) proteins not only lose tumor suppressive function of wild-type p53, but also gain new oncogenic activities to promote tumorigenesis, which is defined as mutp53 gain-of-function (GOF). Maintaining metabolic homeostasis is a novel and critical mechanism of p53 in tumor suppression. Cancer cells often display lipid metabolic reprogramming, which contributes greatly to cancer progression. Currently, the role and mechanism of mutp53 in cancer metabolic reprogramming are poorly defined. Our preliminary studies suggest that mutp53 drives lipid metabolic reprogramming as a critical GOF in CRC cells, and targeting lipid metabolic reprogramming compromises mutp53 GOF in colorectal tumorigenesis. Based on our preliminary results, we hypothesize that GOF mutp53 drives lipid metabolic reprogramming as a critical mechanism to promote colorectal tumorigenesis, which can be targeted for therapy in CRC carrying mutp53. In this proposed study, we will determine the role (Aim 1) and mechanism (Aim 2) of GOF mutp53 in driving lipid metabolic reprogramming in CRC. We will further assess targeting mutp53-driven lipid metabolic reprogramming as a potential therapeutic strategy for CRC carrying mutp53 (Aim 3). The goal of this study is to determine the mechanism of GOF mutp53 in CRC to provide effective targets and strategies for CRC therapy. Metabolic reprogramming and p53 mutations are common events in cancer, and have become extremely attractive targets for cancer therapy. We expect that the results from this proposed study will deepen our understanding of the role and mechanism of mutp53 in metabolic reprogramming and tumorigenesis, and provide the rationale and base for the development of new therapeutic targets and strategies for cancers carrying mutp53.