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Metabolic Study Suggests Glycine Involved in Rapid Cancer Cell Growth

NEW YORK (GenomeWeb News) – Quickly proliferating cancer cells are prone to an uptick in use of the amino acid glycine, a new Science study suggests.

Researchers from the US and Sweden came up with a mass spectrometry-based method called "consumption and release," or CORE, to profile metabolite use in cancer cells from the National Cancer Institute's human cancer cell line panel NCI-60 over time. To round out their metabolic analysis, they also folded in existing data on the expression of more than 1,400 metabolic enzyme-coding genes in the 60 primary cancer cell lines.

Across the lines, which represent nine cancer types, the team saw a surge in glycine consumption in fast-growing cells. In addition, quickly dividing cancer cells had higher-than-usual expression of genes that code for components of a glycine production pathway that operates in the cell's mitochondria.

On the other hand, cancer cells that were either grown in low glycine media or treated with short hairpin RNAs that silenced the mitochondrial glycine synthesis enzyme SHMT2 curbed the growth of quickly dividing cancer cells.

"We have two independent methods — metabolite profiling as well as gene expression profiling — both of which point to glycine metabolism as being important for rate of proliferation," corresponding author Vamsi Mootha, a systems biology researcher affiliated with the Broad Institute, Harvard Medical School, and Massachusetts General Hospital, said in a statement.

Mootha and his team used liquid chromatography and tandem mass spectrometry to track the flow of 219 metabolites moving into and out of cancer cells from the NCI-60 panel over four to five days.

"Using CORE, we can quantitatively determine exactly how much of every metabolite is being consumed or released on a per-cell, per-hour basis," co-first author Mohit Jain, a postdoctoral researcher in Mootha's lab, explained in a statement. "We can now start to derive flux or transport of nutrients into or out of the cell."

For instance, the team tracked 140 metabolites that turned up in fresh media surrounding one or more of the cell lines at the start of the time course or that were released by the lines.

The nature of the metabolites flowing into or out of cells varied with cancer type, researchers reported, with profiles for 111 of the metabolites varying by cell line.

Even so, around one-third of these metabolites were slurped up or spewed out by all of the lines tested. And all of the cell lines were prone to some shared patterns, such as glucose and nutrient uptake and release of related metabolic byproducts.

When they looked specifically at the metabolite use patterns associated with rapid proliferation, though, the investigators found that these cells consistently took up more glycine than usual and released more phosphocholine. In contrast, cancer cells that were growing more slowly tended to release the amino acid.

The team's subsequent expression and gene silencing experiments indicated that the ties between glycine use and speedy cancer cell growth were specifically related to mitochondrial glycine pathways rather than glycine production in the cell's cytosol.

Additional analyses hinted that this mitochondrial glycine pathway might contribute to patient outcomes as well, the study's authors noted, since breast cancer patients with elevated expression of mitochondrial glycine production genes coincided with higher mortality in breast cancer patients tested by microarray in previous studies.

Based on their findings, the researchers speculated that there may be therapeutic potential to targeting metabolic pathways related to glycine production and use. They also noted that the CORE approach for profiling metabolite production and use by cells should be amenable to studying the behavior of a wide range of cell types and situations.

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