@article{a4361770172d482ca3c16b97cc1588df,
title = "A role for p53 in the adaptation to glutamine starvation through the expression of SLC1A3",
abstract = "Numerous 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.",
keywords = "aspartate metabolism, glutamine starvation, p53, SLC1A3",
author = "Myl{\`e}ne Tajan and Hock, {Andreas K.} and Julianna Blagih and Robertson, {Neil A.} and Labuschagne, {Christiaan F.} and Flore Kruiswijk and Humpton, {Timothy J.} and Adams, {Peter D.} and Vousden, {Karen H.}",
note = "Funding Information: We thank Niels J.F. van den Broek, Gillian M. Mackay, and Nathalie Legrave for metabolomic analyses; Billy Clark for RNA-seq; Elodie Kuntz for help with OCR assays; Caroline Zverev and Daiva Poniskaitiene for help with the in vivo studies; and Saverio Tardito and Simone Cardaci for helpful discussions. We are also grateful to Calithera Bioscience for providing CB-839 for in vivo use. This work was funded by Cancer Research UK grants C596/A10419, C596/A26855, and C10652/A16566 and ERC Grant 322842-METABOp53 and was also supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. Funding Information: K.H.V. is on the Board of Directors and a shareholder of Bristol Myers Squibb, on the Science Advisory Board and a shareholder of GRAIL Inc., and on the Science Advisory Board of PMV Pharma and RAZE Therapeutics. She has been in receipt of research funding from Astex Pharmaceuticals and contributed to CRUK Cancer Research Technology filing of Patent Application WO/2017/144877. Funding Information: We thank Niels J.F. van den Broek, Gillian M. Mackay, and Nathalie Legrave for metabolomic analyses; Billy Clark for RNA-seq; Elodie Kuntz for help with OCR assays; Caroline Zverev and Daiva Poniskaitiene for help with the in vivo studies; and Saverio Tardito and Simone Cardaci for helpful discussions. We are also grateful to Calithera Bioscience for providing CB-839 for in vivo use. This work was funded by Cancer Research UK grants C596/A10419 , C596/A26855 , and C10652/A16566 and ERC Grant 322842-METABOp53 and was also supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council , and the Wellcome Trust . Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = nov,
day = "6",
doi = "10.1016/j.cmet.2018.07.005",
language = "English",
volume = "28",
pages = "721--736. E6",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Elsevier B.V.",
number = "5",
}
