p53 and tumor cell metabolism

描述(申请人提供)：本提案旨在确定肿瘤抑制基因P53在新陈代谢调节中的作用，以及该功能丧失在肿瘤发病机制中的后果。P53是人类癌症中突变最频繁的基因，它的失活不仅对多种肿瘤的形成至关重要，而且对肿瘤的持续生存和增殖也是至关重要的。能够理解P53抑制肿瘤发生的机制一直是癌症生物学的中心目标，这对治疗过多的癌症类型具有重要意义。在P53引起的细胞反应中，新的证据表明代谢调节和衰老是肿瘤抑制的关键。肿瘤细胞依靠重新编程的新陈代谢来快速积累生物量，并有效地将氧化损伤降至最低。这项建议的重点是苹果酸酶和异柠檬酸脱氢酶(IDH)。这些是产生还原等量NADPH的主要酶，NADPH对于生物合成和抗氧化防御是必不可少的。它们还与中心代谢中枢三羧酸循环(TCA循环)有关，并可能在葡萄糖代谢中发挥关键作用，特别是谷氨酰胺，这是肿瘤细胞的两种主要营养物质。在我们的初步研究中，我们发现了之前没有预料到的P53和苹果酸酶之间的相互调节。P53抑制苹果酸酶的表达，而苹果酸酶的下调反过来激活P53，调节P53激活的结果，导致衰老。此外，我们还发现，在非应激和特别应激的细胞中，P53抑制IDH1的表达，IDH1是IDH的主要亚型。这些发现表明，P53可能既是NADPH代谢的中心哨兵，也是NADPH代谢的主要调节者，将细胞的代谢状态与细胞命运决定联系在一起。我们计划研究P53和苹果酸酶/IDH1之间的动态相互作用。我们的中心假设是苹果酸酶和P53之间的相互调节，以及P53对IDH1的抑制，调节了生物合成和抗氧化反应，并有助于P53介导的肿瘤抑制。我们提出了三个特定的目标：(1)确定P53和苹果酸酶在谷氨酰胺代谢中的功能；(2)阐明P53在调节IDH1及其相关的代谢通量中的作用；(3)确定苹果酸酶在调节P53激活、抗氧化反应和衰老中的作用。建议的研究将提高我们对代谢调节的关键方面及其与P53介导的细胞命运决定的联系的理解，并可能为将这些NADPH产生酶作为癌症新疗法提供理论基础。

DESCRIPTION (provided by applicant): This proposal aims to define the role of the tumor suppressor p53 in the regulation of metabolism, as well as the consequences of the loss of this function in tumor pathogenesis. p53 holds the distinction of being the most frequently mutated gene in human cancers, and its inactivation is essential not only for the formation of a remarkably wide range of tumors, but also for their continued survival and proliferation. Being able to understand the mechanism by which p53 suppresses tumorigenesis has been a central objective in cancer biology, one which has important implications in the treatment of a plethora of cancer types. Among the cellular response elicited by p53, emerging evidence has indicated that metabolic modulation and senescence are crucial for tumor suppression. Tumor cells rely on re-programmed metabolism to rapidly accumulate biomass and to effectively minimize oxidative damages. This proposal focuses on malic enzyme and isocitrate dehydrogenase (IDH). These are major enzymes that generate the reducing equivalent NADPH, which is essential for biosynthesis and anti-oxidant defense. They are also associated with the tricarboxylic acid cycle (TCA cycle), the central metabolic hub, and likely play critical roles in he metabolism of glucose and especially glutamine, two major nutrients for tumor cells. In our preliminary studies, we found previously unanticipated mutual regulation between p53 and malic enzymes. p53 suppresses the expression of malic enzymes, while down-regulation of malic enzymes reciprocally activates p53 and modulates the outcome of p53 activation, leading to senescence. Furthermore, we found that p53 suppresses the expression of IDH1, a major IDH isoform, in unstressed and especially stressed cells. These findings suggest that p53 may function as both a central sentinel and a master regulator of NADPH metabolism, linking the metabolic state of the cell with the cell fate decision. We plan to investigate the dynamic interplays between p53 and malic enzymes/IDH1. Our central hypothesis is that mutual regulation between malic enzymes and p53, as well as the suppression of IDH1 by p53, modulates biosynthesis and anti-oxidant response, and contributes to p53-mediated tumor suppression. We propose three specific aims: (1) Determine the functions of p53 and malic enzymes in glutamine metabolism; (2) Elucidate the role of p53 in regulating IDH1 and IDH1-assoicated metabolic fluxes; and (3) Define the role of malic enzymes in regulating p53 activation, anti-oxidant response, and senescence. The proposed studies will improve our understanding of key aspects of metabolic regulation and their link to p53-mediated cell fate decision, and may provide a rationale for targeting these NADPH-generating enzymes as a new therapy for cancer.