TY - JOUR TI - Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition AU - Muir, Alexander AU - Danai, Laura V AU - Gui, Dan Y AU - Waingarten, Chiara Y AU - Lewis, Caroline A AU - Vander Heiden, Matthew G A2 - DeBerardinis, Ralph VL - 6 PY - 2017 DA - 2017/08/15 SP - e27713 C1 - eLife 2017;6:e27713 DO - 10.7554/eLife.27713 UR - https://doi.org/10.7554/eLife.27713 AB - 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. KW - cancer KW - metabolism KW - environment KW - glutaminase KW - cystine KW - SLC7A11 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -