Abstract
SummaryNumerous mechanisms to support cells under conditions of transient nutrient starvation have been described. Several functions of the tumor-suppressor protein p53 can contribute to the adaptation of cells to metabolic stress and help cancer cell survival under nutrient-limiting conditions. We show here that p53 promotes the expression of SLC1A3, an aspartate/glutamate transporter that allows the utilization of aspartate to support cells in the absence of extracellular glutamine. Under glutamine deprivation, SLC1A3 expression maintains electron transport chain and tricarboxylic acid cycle activity, promoting de novo glutamate, glutamine, and nucleotide synthesis to rescue cell viability. Tumor cells with high levels of SLC1A3 expression are resistant to glutamine starvation, and SLC1A3 depletion retards the growth of these cells in vitro and in vivo, suggesting a therapeutic potential for SLC1A3 inhibition.
Highlights
Cancer cells are frequently exposed to nutrient- and oxygenlimited environments, resulting from poor vascularization in the developing tumor mass, and there is a growing interest in understanding the metabolic plasticity that supports their survival and proliferation under these conditions
KRas have been shown to alter glutamine metabolism leading to glutamine dependence, the outcome can be strongly tissue and context dependent and some cancer cells produce glutamine from glutamate through a reaction depending on glutamine synthetase (GS) (Tardito et al, 2015)
Glutamine Starvation Activates a Protective p53 Response Previous studies have identified cell lines that differ in their sensitivity to glutamine starvation, as measured by induction of cell death (Cetinbas et al, 2016)
Summary
Cancer cells are frequently exposed to nutrient- and oxygenlimited environments, resulting from poor vascularization in the developing tumor mass, and there is a growing interest in understanding the metabolic plasticity that supports their survival and proliferation under these conditions. Glutamine is the most abundant amino acid in serum, and glutamine levels are often severely depleted in developing cancers (Kamphorst et al, 2015). Glutamine can be used to fuel the tricarboxylic acid (TCA) cycle, a pathway that depends on glutaminase (GLS) to catalyze the production of glutamate from glutamine. Several oncogenes such as Myc and KRas have been shown to alter glutamine metabolism leading to glutamine dependence, the outcome can be strongly tissue and context dependent and some cancer cells produce glutamine from glutamate through a reaction depending on glutamine synthetase (GS) (Tardito et al, 2015). Asparagine has been shown to rescue death in response to glutamine starvation in glutamine-dependent cells (Zhang et al, 2014)
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