Metabolite Profiling Identifies a Key Role for Glycine in Rapid Cancer Cell Proliferation

By Mohit M. Jain, R. Nilsson, Sonia Sharma, Nikhil Madhusudhan, T. Kitami, Amanda L. Souza, Ran Kafri, Marc Kirschner, C. Clish, Vamsi K. Mootha. Science, 2012

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More Glycine, Please To better characterize metabolic properties of cancer cells, Jain et al. (p. 1040; see the Perspective by Tomita and Kami) measured systematically the concentrations of hundreds of metabolites in cell culture medium in which 60 different cancer cell lines were growing. The fastest growing cancer cells tended to consume glycine, whereas more slowly growing cells excreted some glycine. The rapidly growing cancer cells appeared to need glycine for synthesis of purine nucleotides required for continued synthesis of DNA. Interfering with glycine metabolism slowed growth of the rapidly proliferating cancer cells. Thus, an increased dependence on glycine by rapidly growing cancer cells could potentially provide a target for therapeutic intervention. Rapidly growing cancer cells rely on the amino acid glycine to make nucleotides. Metabolic reprogramming has been proposed to be a hallmark of cancer, yet a systematic characterization of the metabolic pathways active in transformed cells is currently lacking. Using mass spectrometry, we measured the consumption and release (CORE) profiles of 219 metabolites from media across the NCI-60 cancer cell lines, and integrated these data with a preexisting atlas of gene expression. This analysis identified glycine consumption and expression of the mitochondrial glycine biosynthetic pathway as strongly correlated with rates of proliferation across cancer cells. Antagonizing glycine uptake and its mitochondrial biosynthesis preferentially impaired rapidly proliferating cells. Moreover, higher expression of this pathway was associated with greater mortality in breast cancer patients. Increased reliance on glycine may represent a metabolic vulnerability for selectively targeting rapid cancer cell proliferation.

Subfields: Biochemistry, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5745770a2e10293711643de5cd904cc8e36ed99e

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Citations in the corpus

Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides (2014, methodology): “The methods described here should be valuable for studying the responses of cancer cells to tumour-relevant concentrations of other highly consumed nutrients, such as amino acids 24 , and to additional compounds that target metabolism.”
Mitochondrial metabolism and cancer (2017, background): “This involves not only increased uptake of glucose (a fraction of which is redirected to the pentose phosphate pathway (PPP) for nucleic acid synthesis and glutathione reduction) [70], but also the ability to process glutamine oxidatively (for energy production via the Krebs cycle and the ETC) or re”
Targeting Metabolism for Cancer Therapy (2017, background): “Glutamine is a non-essential amino acid, and yet cancer cells proliferating in vitro consume glutamine far in excess of any other amino acid and are often dependent on extracellular glutamine for survival (DeBerardinis and Cheng, 2010; Eagle, 1955; Jain et al., 2012).”
Glutathione metabolism in cancer progression and treatment resistance (2018, background): “Interestingly, glycine uptake and catabolism promote tumorigenesis and malignancy, suggesting that glycine metabolism could also be a target for therapeutic intervention (Jain et al., 2012).”
One-Carbon Metabolism in Health and Disease. (2017, background): “High net consumption of serine and glycine is nearly universal across the NCI-60 cancer panel (Jain et al., 2012).”
Glutamine Metabolism in Cancer: Understanding the Heterogeneity (2017, positive): “After glucose, glutamine is the most rapidly consumed nutrient by many human cancer cell lines grown in culture [23,24].”