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.
Tumor growth depends upon the acquisition of gain of function mutations or subjugation of normal growth and survival pathways. Our long-term goal is to identify pathways essential for tumor growth and survival, but non-essential for normal cell maintenance. Our preliminary work suggests that the PERK protein kinase functions in such a pathway and thus may represent a novel therapeutic target.
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