Many tumor cells exhibit high rates of glutamine consumption to support macromolecular biosynthesis and cell proliferation. Glutamine fuels the tricarboxylic acid (TCA) cycle through anaplerosis and contributes to the synthesis of lipids, nucleotides and non-essential amino acids. However, the full spectrum of glutamine contribution to cancer cell growth remains an area of active investigation.
Although glutamine can contribute to synthesis of several amino acids through its catabolism to glutamate, only asparagine requires glutamine for de novo synthesis; glutamine is a substrate for asparagine synthetase (ASNS). ASNS activity is unidirectional and ATP-dependent, suggesting that cells synthesize asparagine at the expense of macromolecule synthesis and cellular energy.
The importance of asparagine for tumor growth has been demonstrated by the effectiveness of extracellular asparaginase in treating low-ASNS-expressing leukaemia. Notably, the off-target glutaminase (GLS) activity of asparaginase is not required for its anti-tumor effects. Although asparaginase is effective as a therapeutic for cancers that obtain the majority of their asparagine from the environment, cancers that are capable of synthesizing asparagine de novo via ASNS are less responsive to asparaginase therapy.
Moreover, leukaemic asparaginase resistance is associated with elevated ASNS expression, and ASNS expression in solid tumous correlates with tumor grade and poor prognosis. Recently, genetic silencing of ASNS in sarcoma cells combined with depletion of plasma asparagine levels via asparaginase was shown to blunt tumor growth in vivo. Thus, cancer cells appear to have high demand for asparagine, and this demand has the potential to be exploited therapeutically.
The nature of ASNS regulation suggests that asparagine may play a role in cellular amino acid homeostasis. ASNS expression is upregulated in response to individual or combined limitation of numerous amino acids, including most essential amino acids. Amino acid-starvation-induced upregulation of ASNS is mediated by activating transcription factor 4 (ATF4), the transcriptional activity of which is activated in response to uncharged tRNAs. Although ATF4 regulates expression of genes involved in multiple amino acid synthesis and transport pathways, asparagine alone rescues the impaired proliferation and autophagy resulting from induced ATF4 knockdown, supporting the idea that asparagine globally impacts intracellular amino acid levels. However, the only currently known function for asparagine is as a substrate for protein synthesis.
Researchers in the journal Nature Communications identify a novel role for asparagine as an amino acid exchange factor. They show that asparagine exchanges with extracellular amino acids to regulate mTOR complex 1 (mTORC1) activation, nucleotide synthesis and proliferation.
Through asparagine synthetase knockdown and altering of media asparagine concentrations, authors show that intracellular asparagine levels regulate uptake of amino acids, especially serine, arginine and histidine. Through its exchange factor role, asparagine regulates mTORC1 activity and protein synthesis.
In addition, researchers show that asparagine regulation of serine uptake influences serine metabolism and nucleotide synthesis, suggesting that asparagine is involved in coordinating protein and nucleotide synthesis. Finally, they show that maintenance of intracellular asparagine levels is critical for cancer cell growth.
These results indicate that glutamine contribution to cancer cell survival and proliferation is, in part, mediated by glutamine-dependent asparagine synthesis.
Amino acid exchange factor and cancer cell proliferation
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