p53-mediated adaptation to serine starvation is retained by a common tumour-derived mutant

Abstract

BackgroundIn response to oncogenic stress, the tumour suppressor protein p53 can induce the elimination of cells through induction of cell death or senescence, helping to restrain malignant progression. Conversely, under nutrient stress, p53 can protect cells by supporting metabolic adaptation. Many cancers express mutant p53 proteins that have lost the cell-elimination properties of wild-type p53. However, a previous report showed that a tumour-derived mutant can retain the ability to support cells under glutamine starvation.ResultsWe show that a commonly occurring p53 mutant, R248W, retains wild-type ability to support survival under serine starvation. R248W, but not R175H, can engage p21 and MDM2, which both function to limit oxidative stress and facilitate the switch to de novo serine synthesis. In vivo, the growth of R248W-expressing tumours is resistant to dietary depletion of serine and glycine, correlating with an increased capacity to limit ROS compared to tumours expressing R175H. Human cancers expressing this p53 mutant show a worse outcome.ConclusionOur work shows that mutant p53s can selectively retain wild-type p53 functions that allow adaptation to serine starvation through the activation of antioxidant defence pathways. Tumours containing this p53 mutation are resistant to serine-limited conditions and less responsive to therapy.Electronic supplementary materialThe online version of this article (10.1186/s40170-018-0191-6) contains supplementary material, which is available to authorized users.

Taking up the reins of power: metabolic functions of p53

“…This leads to the interesting possibility that expression of point mutations that selectively retain wild-type p53 survival functions would be selected more strongly during tumour evolution than mutations that abolish p53 entirely. In support of this suggestion, patients carrying tumours with R248 p53 mutants show a particularly poor survival rate (Xu et al, 2014; Humpton et al, 2018), even compared to patients with tumours harbouring other common p53 mutations.…”

“…Mutant p53 can also promote the mevalonate pathway, so allowing cells to survive under conditions of matrix detachment (Freed-Pastor et al, 2012). Intriguingly, some tumour-associated p53 mutants show selective retention of wild-type functions that contribute to survival under nutrient and oxidative stress (Tran et al, 2017; Humpton et al, 2018). Maintenance of both p21 and MDM2 expression by the hotspot p53 mutant R248, for example, results in an ability to survive glutamine and serine starvation, although this p53 mutant is not able to induce cell death or senescence.…”

Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer

“…For all LC/MS samples, metabolite analysis was performed as described previously (60). Briefly, a Q Exactive Orbitrap mass spectrometer (Thermo Fisher Scientific) was used together with a Thermo Ultimate 3000 HPLC system to analyze prepared samples.…”

p53, cancer and the immune response

“…In this context, the loss of p53 function in tumour cells can make these cells more vulnerable to certain types of metabolic stress (Labuschagne et al, 2018;Lacroix et al, 2019). Many cancers express high levels of point-mutated versions of p53 that generally lose the ability to inhibit cell growth, but in some cases retain survival functions and acquire neomorphic oncogenic activity (Freed-Pastor and Prives, 2012;Humpton et al, 2018;Kim and Lozano, 2018;Tran et al, 2017).…”