SPOT-010 A role for P53 in the adaptation to glutamine starvation through the expression of Slc1a3

Abstract

Introduction Cancer cells are frequently exposed to nutrient and oxygen limited environments, resulting from poor vascularisation in the developing tumour mass, and there is a growing interest in understanding the metabolic plasticity that supports cancer cell 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. Successful tumour development is therefore likely to depend on the ability of tumour cells to withstand glutamine depletion. Analysis of a RNA sequencing experiment comparing the transcriptional profile of cancer cells grown in medium containing all amino acids, or without glutamine revealed that the top pathway induced by glutamine starvation in these cells was p53. We thus asked if the tumour suppressor p53 could play a role in the adaptation of cancer cells to glutamine deprivation. Material and methods We carried out an extensive metabolomics analysis of p53-null HCT116 colorectal cancer cell lines and their corresponding controls exposed to glutamine-free medium and completed this analysis with different technics of cell biology. Results and discussions We showed that p53 was transiently induced upon glutamine withdrawal and that p53-null HCT116 lines failed to proliferate and showed decreased viability under glutamine starvation. This pro-survival role of p53 correlates with its ability to maintain TCA cycle activity and mitochondrial respiration, promoting de novo glutamate and glutamine synthesis to improve cell viability and proliferation. Mechanistically, p53 appears to mediates its effect by supporting aspartate utilisation through the induction of the glutamate aspartate transporter Slc1a3. Interestingly, this transporter is induced under glutamine withdrawal in a wide range of cancer cell lines and strongly supports their ability to grow in glutamine-free condition. Conclusion This study reveals a new role for the duo p53 and its target Slc1a3 in helping cancer cells to survive glutamine deprivation, highlighting a new metabolic vulnerability of cancer cells exposed to glutamine limitation that might be targeted for therapy.