Asparagine and its Influence upon Cancer Cell Community

Asparagine and its Influence upon Cancer Cell Community

Cancer cells defy the most fundamental rules that define cells and their behavior. Ranging from overexpression of Ras and Myc oncogenes to degradation of p53 tumor suppressors, cancer cells exhibit wide range of phenotypes that continuously surprise many researchers on a daily basis. Our current understanding of normal cell biology is derived from these transgressions. Cancer research has been burgeoning over the past few decades, and we now begin to appreciate the complexity of our body concerning the molecular feedback mechanism and how one such error can correspond to ultimate collapse of an organism.

One particularly remarkable feature of cancer cells is their metabolism. Normal cells possess a regulated balance between catabolic (breakdown of molecules) and anabolic (biosynthesis of molecules, often with energy expenses) processes. For example, glycolysis (the breakdown of sugar) and gluconeogenesis (sugar biosynthesis) are two opposing processes that must be heavily coordinated both in terms of time and location. Suppose we consumed a donut for breakfast this morning. Our blood glucose levels will escalate, allowing our pancreas to secrete high amounts of insulin into our bloodstream. Insulin is a hormone that triggers somatic tissues to uptake excess glucose from the bloodstream and use it as a fuel to produce ATP. On the other hand, during hypoglycemia, where blood glucose levels are low, the pancreas releases glucagon, which stimulates liver cells to catabolize stored glycogen and release glucose contents into the bloodstream, maintaining a steady glucose concentration.

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Many cancer cells love to disturb the metabolic homeostasis by shifting the physiological metabolic flux, often towards a more anabolic state. In particular, many cancer cells tends to reprogram their metabolism by elevating expression of enzymes found in nucleotide biosynthesis (Because cancer cells favor uncontrolled DNA replication, they demand high levels of nucleotides). Researchers in Christofk Laboratory in the Department of Molecular and Medical Pharmacology have recently elucidated how an amino acid, asparagine, can promote cancer cell proliferation.

Asparagine is classified as a nonessential amino acid with a polar side chain, found on the exterior surfaces of proteins. It is synthesized from another amino acid precursor, aspartate, catalyzed by an enzyme asparagine synthetase (ASNS). Prior studies have demonstrated that cancer cells demand large amounts of asparagine. By silencing ASNS and depleting plasma asparagines levels through asparaginase (Catabolizes asparagines back into aspartate) in sarcoma cells, tumor growth in vivo has been abated (Hettmer, S. et al, 2015).

One of the significant experimental discoveries produced by Christofk Lab is the identification of asparagine as an amino-acid exchange factor. Asparagine is transiently imported, then becomes exported, coupled by massive import of other amino acids. In ASNS-knockdown cell culture (impaired production of asparagine), researchers observed net decreased uptake of several amino acids such as serine, arginine, and histidine. Intriguingly, when these cells were supplemented with asparagine, normal import of these amino acids was restored (Krall et. al. 2016).

Lab(Figure credit goes to Christofk Lab)

The fact that asparagine regulates serine import sparks great interest. Serine is a ubiquitous polar amino acid that acts as targets for phosphorylation in many signaling contexts as well as transcriptional control. It is also an important precursor for nucleotide biosynthesis. If we recall that cancer cells like to shift cellular metabolic fate into a biosynthetic fate, it is reasonable to surmise that cancer cells demand high levels of serine. Again, Christofk Lab has performed ASNS knockdown in order to establish a potential connection between asparagine levels and serine metabolism. Upon decreased intracellular asparagine vis ASNS knockdown, researchers observed upregulated expression of enzymes found in serine biosynthetic pathway. This suggests that by decreasing intracellular asparagine (thus, impaired ability of asparagine to exchange extracellular serine), the cell responds by turning on the transcriptional machinery that promotes increased levels of intracellular serine (Krall et. al, 2016).

Christofk Lab has undoubtedly filled in a huge gap within the scientific community’s limited knowledge of cellular metabolome. Often when we study amino acids in our textbook, we are probably only aware of their rudimentary principles, such as the fact that they make up the polypeptide chain. Little do we realize the importance of these monomers and how they contribute to overall cellular stability. We are very excited about Dr. Christofk’s extraordinary discovery of this coordination between two distinct amino acids and we are certainly looking forward to learning more about different levels of amino acid crosstalk in many other settings!

 

References:

Hettmer, S. et al. Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. Elife 4, e09436 (2015)

Krall, Abigail S. et al. “Asparagine Promotes Cancer Cell Proliferation through Use as an Amino Acid Exchange Factor.” Nature Communications 7 (2016): 11457. PMC.

Lehninger AL, Nelson DL, Cox MM (2000). Principles of Biochemistry (3rd ed.). New York: W. H. Freeman. ISBN 1-57259-153-6.

Najjar S (2001). “Insulin Action: Molecular Basis of Diabetes”. Encyclopedia of Life Sciences. John Wiley & Sons. doi:10.1038/npg.els.0001402. ISBN 0470016175.

 

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