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Metabolite Profiling Identifies a Key Role for Glycine in Rapid Cancer Cell Proliferation.
Science. 2012 May 25; 336(6084):1040-4
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15 Jun 2012
New Finding, Novel Drug Target, Technical Advance
DOI: 10.3410/f.716747957.792103009
This study is a new twist on 'dirty old metabolism'. The authors have performed a global survey of the consumption and release of metabolites in the culture medium of NCI-60 cancer cell lines, and then carefully analyzed their data. They show that glycine uptake is associated with rapid cancer cell...Continue reading
This study is a new twist on 'dirty old metabolism'. The authors have performed a global survey of the consumption and release of metabolites in the culture medium of NCI-60 cancer cell lines, and then carefully analyzed their data. They show that glycine uptake is associated with rapid cancer cell proliferation, and that expression of the mitochondrial pathway for glycine biosynthesis is associated with mortality in breast cancer patients. This provocative study may suggest new targets for cancer therapy.
Disclosures
None declared
Add Comment
Matthews R: F1000Prime Recommendation of [Jain M et al., Science 2012, 336(6084):1040-4]. In F1000Prime, 15 Jun 2012; DOI: 10.3410/f.716747957.792103009. F1000Prime.com/716747957#eval792103009
18 Jun 2012
New Finding
DOI: 10.3410/f.716747957.792103110
Cancer cells exhibit a remarkable ability to adapt to new and hostile environments and change metabolic needs. This “metabolic reprogramming” has long been considered a feature of cancer and many studies in the last 5 years have reported accumulation of specific intracellular metabolite pools in several...Continue reading
Cancer cells exhibit a remarkable ability to adapt to new and hostile environments and change metabolic needs. This “metabolic reprogramming” has long been considered a feature of cancer and many studies in the last 5 years have reported accumulation of specific intracellular metabolite pools in several cancer cell lines. This report, by using liquid chromatography-tandem mass spectrometry (LC-MS/MS), analyzes the metabolic profile (219 metabolites, spanning the major pathways of intermediary metabolism) in a collection of 60 characterized human cancer cell lines, established from 9 frequent tumor types (NCI-60 panel). These data have been integrated with existing cancer expression profiles. Among the major pathways of intermediate metabolism, the mitochondrial glycine biosynthetic pathway emerged as a hallmark of proliferation of cancer cells (not normal proliferating cells). Inhibition of glycine uptake or synthesis profoundly affects growth of cancer cells in vitro. Amplification of this pathway apparently correlates with higher mortality rates in breast cancer patients.
Glycine is a non-essential amino acid, which is endogenously synthesized and it is likely, in proliferating cancer cells, that the demand exceeds the synthesis. Also, sarcosine, an N-methyl derivative of glycine, is high during prostate cancer progression and can be detected non-invasively in urine {1}.
Collectively, we are just starting to learn how successful the metabolic “re-programming” during evolution of cancer cells can be {1-3}.
The authors developed a CORE atlas of metabolites (COnsumption and RElease) by analyzing by LS-MS/MS the medium taken before or after 5 days of culture. This analysis can discover relations between metabolites and identify signatures of cell types and cancer types. For example, CORE identified leukemia cells (ornitine release) from melanoma cells (adenosine and inosine release). The first result of this type of analysis was that, in all cancer lines, the carbon consumption was tightly correlated to carbon release, indicating a common metabolic phenotype: partial or incomplete catabolism and release of by-products.
The most striking CORE profile was that of glycine: it was consumed by growing cells and released by slowly proliferating cells. Normal, NOT-transformed, even rapidly proliferating, cells (comparable to the most rapidly growing tumor cells) released, rather than consumed, glycine. Expression analysis of 1425 metabolic enzymes in the 60 cell lines reveals that the enzymes of glycine biosynthesis (mainly, the mitochondrial pathway) are over expressed in rapidly proliferating tumor cell lines. The mitochondrial pathway is formed by the glycine synthesizing enzyme, SHMT2 (serine hydroxymethyltransferase), induced by the oncogene c-Myc, and by the enzymes MTHFD2 and 1L (5,10-methylene tetrahydrofolate dehydrogenase), which regenerate tetrahydrofolate, the central element in one-carbon unit transfer. Silencing of SHMT2, in the absence of glycine inhibits proliferation, which is rescued by the addition of glycine, NOT by formate, a source of one-carbon unit.
Metabolic tracing with 13 C-glycine shows that glycine is incorporated into purine nucleotides and glutathione in growing cells. Inhibition of glutathione does not seem important for proliferation, because previous large scale chemo-sensitivity profiling indicates that inhibition of glutathione synthesis does not correlate with proliferation rate, as well as the inhibition of de novo purine synthesis.
The levels of expression of the mitochondrial glycine biosynthetic enzymes above the median in a large cohort (totaling 1300 patients with early breast cancer followed for survival) was associated with higher mortality and an overall hazard ratio of 1.82, similar to those associated with tumor grade or lymph node status.
Glycine biosynthesis seems a metabolic mark of rapidly proliferating cancer cells and may be relevant not only for “pervasive” purine metabolism–DNA synthesis, but also for methylation-demethylation reactions of histones and DNA using one-carbon transfer.
It is possible that we are looking at a general type of transcription program, which adapts tumor cells to nutrient-energy stress {2,3}.
NB - I am listed as an author on ref. {3}, below.
Glycine is a non-essential amino acid, which is endogenously synthesized and it is likely, in proliferating cancer cells, that the demand exceeds the synthesis. Also, sarcosine, an N-methyl derivative of glycine, is high during prostate cancer progression and can be detected non-invasively in urine {1}.
Collectively, we are just starting to learn how successful the metabolic “re-programming” during evolution of cancer cells can be {1-3}.
The authors developed a CORE atlas of metabolites (COnsumption and RElease) by analyzing by LS-MS/MS the medium taken before or after 5 days of culture. This analysis can discover relations between metabolites and identify signatures of cell types and cancer types. For example, CORE identified leukemia cells (ornitine release) from melanoma cells (adenosine and inosine release). The first result of this type of analysis was that, in all cancer lines, the carbon consumption was tightly correlated to carbon release, indicating a common metabolic phenotype: partial or incomplete catabolism and release of by-products.
The most striking CORE profile was that of glycine: it was consumed by growing cells and released by slowly proliferating cells. Normal, NOT-transformed, even rapidly proliferating, cells (comparable to the most rapidly growing tumor cells) released, rather than consumed, glycine. Expression analysis of 1425 metabolic enzymes in the 60 cell lines reveals that the enzymes of glycine biosynthesis (mainly, the mitochondrial pathway) are over expressed in rapidly proliferating tumor cell lines. The mitochondrial pathway is formed by the glycine synthesizing enzyme, SHMT2 (serine hydroxymethyltransferase), induced by the oncogene c-Myc, and by the enzymes MTHFD2 and 1L (5,10-methylene tetrahydrofolate dehydrogenase), which regenerate tetrahydrofolate, the central element in one-carbon unit transfer. Silencing of SHMT2, in the absence of glycine inhibits proliferation, which is rescued by the addition of glycine, NOT by formate, a source of one-carbon unit.
Metabolic tracing with 13 C-glycine shows that glycine is incorporated into purine nucleotides and glutathione in growing cells. Inhibition of glutathione does not seem important for proliferation, because previous large scale chemo-sensitivity profiling indicates that inhibition of glutathione synthesis does not correlate with proliferation rate, as well as the inhibition of de novo purine synthesis.
The levels of expression of the mitochondrial glycine biosynthetic enzymes above the median in a large cohort (totaling 1300 patients with early breast cancer followed for survival) was associated with higher mortality and an overall hazard ratio of 1.82, similar to those associated with tumor grade or lymph node status.
Glycine biosynthesis seems a metabolic mark of rapidly proliferating cancer cells and may be relevant not only for “pervasive” purine metabolism–DNA synthesis, but also for methylation-demethylation reactions of histones and DNA using one-carbon transfer.
It is possible that we are looking at a general type of transcription program, which adapts tumor cells to nutrient-energy stress {2,3}.
NB - I am listed as an author on ref. {3}, below.
References
1.
Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
Nature. 2009 Feb 12; 457(7231): 910-4
PMID: 19212411
DOI: 10.1038/nature07762
2.
AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress.
Nature. 2012 May 31; 485(7400): 661-5
PMID: 22660331
DOI: 10.1038/nature11066
3.
Activation of β-Catenin by Oncogenic PIK3CA and EGFR Promotes Resistance to Glucose Deprivation by Inducing a Strong Antioxidant Response.
PLoS One. 2012; 7(5): e37526
PMID: 22662165
DOI: 10.1371/journal.pone.0037526
Disclosures
None declared
Avvedimento E: F1000Prime Recommendation of [Jain M et al., Science 2012, 336(6084):1040-4]. In F1000Prime, 18 Jun 2012; DOI: 10.3410/f.716747957.792103110. F1000Prime.com/716747957#eval792103110
19 Jun 2012
New Finding
DOI: 10.3410/f.716747957.792203037
The authors determined profiles of the consumption and release (CORE) of 219 metabolites from 60 primary human cancer cell lines and correlated these data with cancer cell proliferation. Surprisingly, increased consumption of glycine, a non-essential amino acid, was observed for highly proliferating cells...Continue reading
The authors determined profiles of the consumption and release (CORE) of 219 metabolites from 60 primary human cancer cell lines and correlated these data with cancer cell proliferation. Surprisingly, increased consumption of glycine, a non-essential amino acid, was observed for highly proliferating cells and release of glycine was observed for slowly proliferating cells. The contribution of glycine metabolism to rapid cell proliferation was further supported by genetic silencing and nutrient deprivation studies. It was concluded that glycine metabolism could be a therapeutic target to combat rapidly proliferating cancer cells.
There is no shortage of possible therapeutic targets for cancer. However, potential targets that may be effective against many different forms of cancer are less common. A focus of studies such as this one on the alterations of metabolism that occur as a consequence of cancer provides insight into how it may be possible to develop therapies that could be effective against cancer in general.
There is no shortage of possible therapeutic targets for cancer. However, potential targets that may be effective against many different forms of cancer are less common. A focus of studies such as this one on the alterations of metabolism that occur as a consequence of cancer provides insight into how it may be possible to develop therapies that could be effective against cancer in general.
Disclosures
None declared
Davidson V: F1000Prime Recommendation of [Jain M et al., Science 2012, 336(6084):1040-4]. In F1000Prime, 19 Jun 2012; DOI: 10.3410/f.716747957.792203037. F1000Prime.com/716747957#eval792203037
F1000Prime Recommendations, Dissents and Comments for [Jain M et al., Science 2012, 336(6084):1040-4]. In F1000Prime, 23 May 2013; F1000Prime.com/716747957
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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.
PMID: 22628656
