Abstract
Many mammalian cancer cell lines depend on glutamine as a major tri-carboxylic acid (TCA) cycle anaplerotic substrate to support proliferation. However, some cell lines that depend on glutamine anaplerosis in culture rely less on glutamine catabolism to proliferate in vivo. We sought to understand the environmental differences that cause differential dependence on glutamine for anaplerosis. We find that cells cultured in adult bovine serum, which better reflects nutrients available to cells in vivo, exhibit decreased glutamine catabolism and reduced reliance on glutamine anaplerosis compared to cells cultured in standard tissue culture conditions. We find that levels of a single nutrient, cystine, accounts for the differential dependence on glutamine in these different environmental contexts. Further, we show that cystine levels dictate glutamine dependence via the cystine/glutamate antiporter xCT/SLC7A11. Thus, xCT/SLC7A11 expression, in conjunction with environmental cystine, is necessary and sufficient to increase glutamine catabolism, defining important determinants of glutamine anaplerosis and glutaminase dependence in cancer.
Highlights
Altered metabolism is a hallmark of cancer (Hanahan and Weinberg, 2011) and reflects the increased energetic and biosynthetic demands of proliferating cancer cells (DeBerardinis and Chandel, 2016; Vander Heiden and DeBerardinis, 2017)
We examined glutamine metabolism in mutant KRAS-driven human A549 lung cancer cells cultured in multiple environments
We found a strong correlation between cystine-induced glutamine anaplerosis and xCT/SLC7A11 mRNA expression reported by the Cancer Cell Line Encyclopedia (CCLE) (Barretina et al, 2012), suggesting that cystine levels and xCT/SLC7A11 expression contribute to the prominent use of glutamine as a anaplerotic TCA cycle substrate in many cancer cells in culture (Figure 4F)
Summary
Altered metabolism is a hallmark of cancer (Hanahan and Weinberg, 2011) and reflects the increased energetic and biosynthetic demands of proliferating cancer cells (DeBerardinis and Chandel, 2016; Vander Heiden and DeBerardinis, 2017). Consistent with this, many cancer cell lines depend on extracellular glutamine for proliferation in vitro, even though glutamine is nominally non-essential and can be synthesized from other nutrients. This contributed to the concept that some cancer cells are glutamine addicted (Altman et al, 2016; Wise and Thompson, 2010). Glutamine can be used to support proliferation in multiple ways It is a proteinogenic amino acid, can act as a nitrogen donor for the synthesis of amino acids as well as nucleotides, and glutamine can contribute carbon to the TCA cycle to replace cycle intermediates that are removed for the production of biomass, a process termed anaplerosis (Altman et al, 2016; Daye and Wellen, 2012; DeBerardinis and Cheng, 2010; Hensley et al, 2013). Analysis of the fate of glutamine nitrogen in proliferating cancer cells in vitro suggests that most glutamine nitrogen is excreted as ammonia and alanine, suggesting that the high rate of glutamine consumption is not due to nitrogen demand
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