Metabolism, protein and miRNA cross-talk in cell cycle and tumor progression

描述(由申请人提供)：在肿瘤疾病中，持续增殖、侵袭和转移的细胞重新编程对于肿瘤的启动和发展是必不可少的。增加对癌基因调控这些过程的了解是成功治疗的关键。我们的研究集中在改变的生物能量和生物合成代谢在癌基因c-Myc调控的细胞周期进入和肿瘤进展中的重要作用。我们最近开发了一种新的方法来跟踪营养物质的代谢及其对蛋白质修饰的直接贡献，并证明了在Myc依赖的细胞周期进入过程中，通过底物供应来调节组蛋白乙酰化，这是代谢和翻译后修饰之间的一种以前不为人知的联系。Myc表达细胞中脂质生物合成的增加可能会增加针对脂筏的蛋白质，我们的初步研究表明，在Myc诱导的细胞周期进入过程中，RAFT相关的RAS蛋白增加。我们还证实了培养液中前列腺素E_2的增加，环氧合酶抑制剂对Myc表达的细胞具有选择性的抗增殖作用。最后，我们用Myc可诱导/可消退肿瘤模型进行的稳定同位素研究表明，肿瘤的启动、进展和消退与代谢流量的明显变化有关，这为Myc失活后饱和脂肪酸的内源性脂毒性奠定了基础。这些结果使我们假设Myc在促进细胞周期和细胞生长的协同途径中引导新陈代谢，这种整合的丧失是Myc癌基因成瘾的原因之一。我们提出以下具体目标来解决这些假设。具体目的1.分析Myc依赖的细胞周期进入过程中脂筏成分的变化。具体目的2.分析依赖Myc的细胞周期进入过程中花生四烯酸代谢的需要。具体目的3.确定脂毒性在Myc癌基因成瘾中的作用。总之，这些研究有可能改变目前关于信号网络控制的范式，提供对参与细胞从静止状态到增殖状态和致瘤状态的编程过程中细胞命运变化的蛋白质和miRNAs的洞察，并揭示癌基因成瘾的潜在机制。

DESCRIPTION (provided by applicant): In neoplastic diseases, cellular reprogramming for continued proliferation, invasion and metastasis are essential for tumor initation and progression. An increased understanding of oncogene regulation of these processes is essential to successful therapy. Our research has focused on the essential role of altered bioenergetics and biosynthetic metabolism during cell cycle entry and tumor progression regulated by the oncogene c-Myc. We have recently developed a novel approach to trace metabolism of nutrients and their direct contribution to protein modifications and demonstrated regulation of histone acetylation by substrate supply during Myc-dependent cell cycle entry, a previously unappreciated connection between metabolism and post-translational modifications. Increased lipid biosynthesis in Myc-expressing cells may increase protein targeting to lipid rafts and our preliminary studies indicate increased raft-associated Ras protein during Myc- induced cell cycle entry. We also demonstrated increased prostaglandin E2 in media, and that cyclooxygenase inhibitors had selective anti-proliferative effects for Myc-expressing cells. Lastly, our stable isotope studies with a Myc inducible/regressible tumor model show that tumor initiation, progression and regression are associated with distinct alterations in metabolic flux, setting up a potential for endogenous lipotoxicity from saturated fatty acids after Myc inactivation. These results lead us to hypothesize that Myc directs metabolism in synergistic pathways to promote cell cycling and cell growth, and that loss of this integration is a cause of Myc oncogene addiction. We propose the following specific aims to address these hypotheses. Specific Aim 1. To analyze changes in lipid raft composition during Myc-dependent cell cycle entry. Specific Aim 2. To analyze the requirements for arachidonic acid metabolism during Myc-dependent cell cycle entry. Specific Aim 3. To determine the role of lipotoxicity in Myc oncogene addiction. Together these studies have the potential to change current paradigms regarding control of signaling networks, to provide insight into proteins and miRNAs that participate in alteration of cell fates during programming of cells from quiescent to proliferative and tumorigenic states, and to reveal mechanisms underlying oncogene addiction.