Journal Article

Modulating the therapeutic response of tumours to dietary serine and glycine starvation

Athineos, Dimitris, Maddocks, Oliver D. K., Campbell, Kirsteen J., Vousden, Karen H., Vincent, David F., Ceteci, Fatih, Kruiswijk, Flore, Cheung, Eric C., Mackay, Gillian M., Lee, Pearl, van den Broek, Niels J. F., Sansom, Owen J., Gay, David, Blyth, Karen, Zhang, Tong, Blagih, Julianna, Labuschagne, Christiaan F.

2017

Overview

Dependence on exogenous serine means that tumour growth is restricted in mice on a low-serine diet; this effect on tumour growth can be amplified by antagonizing the antioxidant response. Exploring dietary restrictions in cancer therapy Tumours acquire different metabolic adaptations to foster accelerated growth. This can lead to their dependence on crucial nutrients for anabolism. It had been shown that some non-essential amino acids, including serine, are required for tumour growth in mice. This report explores the effect of serine deprivation in endogenous tumour mouse models, uncovering how different oncogenic adaptations lead tumours to rely on exogenous serine or upregulate its cellular synthesis. Dependence on exogenous serine renders tumours sensitive to serine-deprivation diets, and this effect on tumour growth can be amplified by antagonizing the anti-oxidant response. The authors take a step towards dissecting how the metabolic vulnerabilities of cancer may be explored therapeutically in the future. The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1 ). While some cancer cells upregulate de novo serine synthesis 2 , 3 , 4 , many others rely on exogenous serine for optimal growth 5 , 6 , 7 . Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models 7 , 8 . Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 38 / 631/67/1059 / 631/67/2327 / 64 / 64/110 / 82 / 82/80 / Amino acids / Animals / Antioxidants - metabolism / Apoptosis / Biguanides - pharmacology / Cell Line, Tumor / Diet / Disease Models, Animal / Enzymes / Female / Food Deprivation / Gangrene / Glucose / Glycine - deficiency / Glycine - metabolism / Humanities and Social Sciences / Humans / Intestinal Neoplasms - diet therapy / Intestinal Neoplasms - genetics / Intestinal Neoplasms - metabolism / Intestinal Neoplasms - pathology / letter / Lymphoma / Lymphoma - diet therapy / Lymphoma - metabolism / Lymphoma - pathology / Male / Mice / Mitochondria - drug effects / Mitochondria - metabolism / multidisciplinary / Nutritional Status / Oxidative Phosphorylation - drug effects / Pancreatic Neoplasms - diet therapy / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - metabolism / Phosphorylation / Proto-Oncogene Proteins p21(ras) - genetics / Science / Serine - biosynthesis / Serine - deficiency / Serine - metabolism / Serine - pharmacology / Survival Rate / Tumors