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。 p53 在人类癌症中经常发生突变， 包括结直肠癌（CRC）。许多突变的p53（mutp53）蛋白不仅失去肿瘤抑制作用 野生型p53的功能，而且还获得新的致癌活性以促进肿瘤发生，这被定义为 mutp53 功能增益 (GOF)。维持代谢稳态是 p53 的一种新颖且关键的机制 肿瘤抑制。癌细胞经常表现出脂质代谢重编程，这极大地促进了 癌症进展。目前，mutp53在癌症代谢重编程中的作用和机制有： 定义不明确。我们的初步研究表明，mutp53 驱动脂质代谢重编程是一个关键因素。 CRC 细胞中的 GOF，以及靶向脂质代谢重编程会损害结直肠中的 mutp53 GOF 肿瘤发生。根据我们的初步结果，我们假设 GOF mutp53 驱动脂质代谢 重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CRC中携带mutp53。在这项拟议的研究中，我们将确定其作用（目标 1）和机制（目标 2） GOF mutp53 在驱动 CRC 脂质代谢重编程中的作用。我们将进一步评估针对 mutp53 驱动的目标 脂质代谢重编程作为携带 mutp53 的 CRC 的潜在治疗策略（目标 3）。目标 本研究的目的是确定GOF mutp53在CRC中的作用机制，以提供有效的靶点和策略 用于结直肠癌治疗。代谢重编程和 p53 突变是癌症中的常见事件，并且 成为极具吸引力的癌症治疗靶点。我们期望这项拟议研究的结果 将加深我们对mutp53在代谢重编程中的作用和机制的理解 肿瘤发生机制，为新的治疗靶点的开发提供理论依据和基础。 针对携带 mutp53 的癌症的策略。

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.