Regulation of Tumorigenesis by the Perk Kinase

肿瘤细胞的快速扩张可能会导致微环境，在这种微环境中，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过了组织的既定血管。在正常细胞中，营养物质供应的限制会引发生长停滞和/或细胞凋亡，从而阻止细胞在这种条件下扩张。这项建议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。在前一个资助期进行的工作支持这样一种模型，即依赖于PERK的信号防止活性氧物种积累，从而防止对肿瘤细胞的氧化损伤，同时促进对肿瘤生长至关重要的脂质生物合成增加。根据我们的初步数据，我们假设PERK作为细胞营养供应的传感器，通过激活转录程序来发挥关键的促生存因子的作用，该转录程序促进细胞对营养限制的适应，从而促进肿瘤的生长和生存。为了验证这一假说，我们提出了三个目标。在目标1中，我们将使用基于细胞的方法和动物模型来确定肿瘤启动或维持是否需要PERK。目标2中的实验将评估依赖于PERK的氧化还原稳态调节对肿瘤生长和生存的贡献。在最终目标，目标3，我们将确定依赖于PERK的调节脂质生物合成途径对肿瘤生长和增殖的作用。有很明显的 这项建议和项目1之间的相互作用点，因为我们已经合作证明，PERK调节脂肪酸和脂肪的生物合成，这有望有助于肿瘤发展过程中的生物能量平衡；该项目和项目2作为PERK，有助于经历严重缺氧的细胞的细胞平衡和氧化还原控制。通过该计划促进的合作，我们将使用细胞培养和动物模型来研究营养限制(项目2)调节细胞对氧化还原稳态变化的反应的机制。我们将调查营养素是如何 剥夺(项目1)通过PERK影响肿瘤生物能量学和脂质的产生。这些合作努力的性质将提供关于在肿瘤进展过程中被颠覆的新的调控相互作用的信息。这些发现将为设计新的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.