An early effect of dysregulated cancer growth is the accumulation of malignant cells in excess of the physiological numbers that can be supported by the existing vascular system. As a result, developing tumors are subject to a combination of oxygen limitation and nutrient deprivation. Under such conditions, the accumulation of non-transformed cells is limited because hypoxia and/or nutrient depletion leads to the initiation of apoptosis. In contrast, most tumor cells are defective in their apoptotic response and, as a result, fail to respond to hypoxia and/or nutrient limitations through apoptosis. The goal of this project is to identify metabolic pathways that allow tumor cells to adapt and grow under conditions of nutrient and/or oxygen limitation.
Two Specific Aims are envisioned. In the first Specific Aim, we will examine the regulation of lipid synthesis and degradation under conditions of glucose depletion. In this Aim, we hope to gain insight into how tumor cells growing under glucose limitation can simultaneously activate fatty acid oxidation to support ATP production while maintaining the net fatty acid synthesis required for cell growth. Engaging in the simultaneous synthesis and catabolism of fatty acids puts the cell at risk of engaging in a potentially fatal futile cycle. In the second Specific Aim, we hope to determine the metabolic adaptations that support hypoxic cell survival and lipid synthesis. We will investigate how hypoxic tumor cells maintain viability and lipid synthesis despite the fact that HIF-1 a activation results in diversion of available glucose into anaerobic glycolysis. The studies of Specific Aim 1 should provide information that will contribute to the success of Projects 2 and 3. The proposed studies will provide insights into the molecular mechanisms by which cells maintain a viable ATP/ADP ratio while maintaining macromolecular synthesis under suboptimal conditions of glucose availability. In turn, the success of the studies proposed in Specific Aim 2 are dependent in part on the expertise and reagents available from Projects 2 and 3, and are also likely to benefit from insights derived from the ongoing results of these projects. Through these collaborative studies, we wish to gain insight into how both transformed and non-transformed cells not only survive but grow under conditions of oxygen and/or nutrient deprivation. As a result of the proposed investigations, we hope to identify ways to impair/augment these survival strategies to enhance the efficacy of existing cancer therapy while preserving the survival and recovery of non-transformed cells.
Growing cells depend on higher levels of nutrient and oxygen utilization than quiescent cells, yet cancer cells are able to survive and continue to proliferate under conditions of nutrient depletion and hypoxia that would otherwise result in the apoptotic cell death of non-transformed cells. In this project we propose to identify the pathways cancer cells utilize to survive and grow in the face of non-physiologic levels of oxygen or nutrients.
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