SHIRLEY, OCT 30th,2017 – A new finding, published in the Journal Science on Oct 12th, showing that breast tumor cells recycle ammonia metabolism which can accelerate the proliferation of breast tumor cells, so that repressing ammonia metabolism can stunt tumor cells growth which informs design of new therapies.
“Classically, ammonia was thought to be metabolic waste that must be cleared due to its high toxicity,” said senior study author Marcia Haigis, associate professor of cell biology at HMS. “We found that not only was ammonia not toxic for breast cancer cells, it could be used to feed tumors by serving as a source for the building blocks that tumors need to grow.”
The cells (especially tumor cells) have a large nutrient consumption and produce excess metabolic wastes, of which ammonia is usually transported to the liver through blood vessels, converted to less toxic substances in the liver, and excreted from urine. However, few blood vessels around the tumor, ammonia will accumulate in the local environment, which is fatal for many cells.
In order to explore how tumors respond to high concentrations of ammonia, Haigis and his team use a technique to label nitrogen on glutamine, and when glutamine is decomposed during metabolic processes, the labeled nitrogen is released to the byproduct ammonia. The researchers analyzed more than 200 different cellular metabolites in breast cancer cells and human tumor xenograft mouse models with this tracing method.
Researchers finally found that tumor cells can efficiently recover ammonia and incorporate nitrogen in the ammonia into other compounds. Especially the the amino acid glutamate, which is an essential component of protein and other derivatives. About 20% of all glutamate in the cells are from the recovered nitrogen source (ammonia).
In 3D cell culture experiments which allow cells to split in all directions, showing that high concentrations of ammonia can accelerate the growth of breast tumor cells. Ammonia-exposed cells doubled up seven hours faster than cells grown without ammonia. At the same time, ammonia exposure also increased the surface area of cells and cell clusters by up to 50 percent compared with cells grown without ammonia.
The researchers inhibited the catalytic reduction of glutamate dehydrogenase (GDH) to form glutamate on a-ketoglutaric acid, which was significantly reduced in tumor growth.
“We found that repressing ammonia metabolism stunts tumor growth in mice,” said Jessica Spinelli, a graduate student in the Haigis lab and first author on the study. “Therefore, inhibition of ammonia assimilation or ammonia production may be rational strategies for therapy design.”
The results of this paper show that the biological effects of ammonia should be reassessed. They can be used as a nutrient necessary for the nutrition of the tumor, indicating a new direction for stunning tumor growth. Researchers are exploring the therapeutic significance of ammonia metabolism in breast cancer.
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