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

Abstract

Metabolic reprogramming has been proposed to be a hallmark of cancer, yet we currently lack a systematic characterization of the metabolic pathways active in transformed cells. Using mass spectrometry, we measured the consumption and release (CORE) of 219 metabolites from media across the NCI-60 cancer cell lines, and integrated CORE profiles with a pre-existing atlas of gene expression. The integrated 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.

Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion

“…The high expression of MTHFD2 in breast cancer, as well as the association between the levels of this enzyme and poor patient prognosis, demonstrate that altered function of this enzyme confers selective advantages to tumors 2,10,12,13 . However, recent data indicate that MTHFD2 also possesses non-metabolic functions 16 .…”

Uncovering metabolism in rhabdomyosarcoma

“…Cysteine transport is under the control of the glutamate-cystine xCT transporter, 101,102 whereas the availability of glutamate depends on activity of glutaminase, target of p53 and Myc factors. Glycine is not only a component of GSH, but also represents a major source for biosynthesis of purines and heme group, 103 and of methyl groups for the socalled one-carbon metabolism, a complex network that based on folate compounds, well-known targets of antifolate chemotherapy. The GSH-dependent antioxidant response of cancer cells may benefit depending on the availability of serine, which can be transformed into glycine through the serine hydroxymethyltransferase (SHMT).…”

Targeting MTHFD2 in acute myeloid leukemia

“…Heiden et al, 2010). Additionally, the discovery of the critical importance of glycine and serine in cancer metabolism has led to a resurgence in interest in better understanding the mechanistic relevance of one-carbon folate metabolism (Jain et al, 2012;Zhang et al, 2012;Labuschagne et al, 2014;Kim et al, 2015;Maddocks et al, 2016).…”