Serine starvation induces stress and p53 dependent metabolic remodeling in cancer cells

Cancer cells acquire distinct metabolic adaptations to survive stress associated with tumour growth and to satisfy the anabolic demands of proliferation. The tumour suppressor protein p53 influences a range of cellular metabolic processes, including glycolysis(1,2) oxidative phosphorylation(3) (OXPHOS), glutaminolysis(4,5) and anti-oxidant response(6). In contrast to its role in promoting apoptosis during DNA damaging stress, p53 can promote cell survival during metabolic stress(7), a function that may contribute not only to tumour suppression but also to non-cancer associated functions of p53(8). Here we show that cancer cells rapidly utilise exogenous serine and that serine deprivation triggered activation of the serine synthesis pathway (SSP) and rapidly suppressed aerobic glycolysis, resulting in increased flux to the TCA cycle. Transient p53-p21 activation and cell cycle arrest promoted cell survival efficiently channelling depleted serine stores to glutathione synthesis, preserving cellular anti-oxidant capacity. Cells lacking p53 failed to complete the response to serine depletion, resulting in oxidative stress, reduced viability and severely impaired proliferation. The role of p53 in supporting cancer cell proliferation under serine starvation was translated to an in vivo model, suggesting that serine depletion has a potential role in the treatment of p53-deficient tumours.