Regulation of Tumorigenesis by the Perk Kinase

肿瘤细胞的快速扩张可能会导致微环境，其中葡萄糖、氧气和生长因子等代谢营养物质变得有限，因为细胞体积扩张超出了组织的既定血管分布。在正常细胞中，营养物质可用性的限制触发生长停滞和/或凋亡，从而防止在这种条件下的细胞扩增。本提案的目的是确定内质网相关激酶PERK在营养限制条件下调节肿瘤细胞适应和肿瘤生长中的作用。在上一个资助期间进行的工作支持一个模型，其中PERK依赖性信号防止活性氧的积累，从而防止对肿瘤细胞的氧化损伤，同时促进脂质生物合成增加，这对肿瘤生长至关重要。基于我们的初步数据，我们假设PERK作为细胞营养可用性的传感器，通过激活转录程序作为关键的促生存因子发挥作用，该转录程序促进细胞适应营养限制，从而促进肿瘤生长和存活。为了验证这一假设，提出了三个目标。在目标1中，我们将使用基于细胞的方法以及动物模型来确定PERK是否是肿瘤起始或肿瘤维持所需的。目标2中的实验将评估PERK依赖性调节氧化还原稳态对肿瘤生长和存活的贡献。在最后的目标，目标3，我们将确定PERK依赖性调节脂质生物合成途径对肿瘤生长和增殖的作用。存在明显 我们已经合作证明，PERK调节脂肪酸和脂质生物合成，这有望有助于肿瘤发展期间的生物能量稳态;与此项目和项目2相比，PERK有助于经历严重缺氧的细胞中的细胞稳态和氧化还原控制。通过该项目促进的合作，我们将研究营养限制（项目2）调节细胞反应的机制，使用细胞培养和动物模型改变氧化还原稳态。我们将研究如何营养 剥夺（项目1）影响肿瘤生物能量学和PERK的脂质产生。这些合作努力的性质将提供关于肿瘤进展期间被破坏的新的调节相互作用的信息。本文所揭示的发现将为设计新型抗癌疗法提供必要的基础。

The rapid expansion of tumor cells can result in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as cellular volume expands beyond the established vascularity of the tissue. In normal cells, limits in nutrient availability trigger growth arrest and/or apoptosis thereby preventing cellular expansion under such conditions. The goal of this proposal is to determine the role of the endoplasmic reticulum associated kinase, PERK, in the regulation of tumor cell adaptation and tumor growth during conditions of nutrient limitation. Work performed during the previous funding period supports a model wherein PERK-dependent signals prevent the accumulation of reactive oxygen species thereby preventing oxidative damage to tumor cells while simultaneously promoting increased lipid biosynthesis, which is essential for tumor growth. Based on our preliminary data, we hypothesize that PERK, as a sensor of cellular nutrient availability, functions as a critical pro-survival factor via activation of a transcriptional program that promotes cellular adaptation to nutrient restriction thereby facilitating tumor growth and survival. To test this hypothesis, three aims are proposed. In Aim 1, we will determine whether PERK is required for tumor initiation or tumor maintenance using both cell based approaches as well as animal models. Experiments in Aim 2 will assess the contribution of PERK-dependent regulation of redox homeostasis for tumor growth and survival. In the final aim, Aim 3, we will determine the role of PERK-dependent regulation of lipid biosynthetic pathways to tumor growth and proliferation. There are obvious points of cross-talk between this proposal and Project 1 as we have collaboratively demonstrated that PERK regulates fatty acid and lipid biosynthesis, which is expected to contribute to bioenergetic homeostasis during tumor development; with this project and Project 2 as PERK contributes to cellular homeostasis and redox control in cells experiencing severe hypoxia. Through collaborations facilitated by this program, we will investigate the mechanisms whereby nutrient limitation (Project 2) regulates cellular response to alterations in redox homeostasis using cell culture and animal models. We will investigate how nutrient deprivation (Project 1) impinges upon tumor bioenergetics and lipid production by PERK. The nature of these cooperative efforts will provide information regarding novel regulatory interactions that are subverted during neoplastic progression. The findings that are revealed herein will provide the foundation necessary for the design of novel anti-cancer therapeutics.