Asparagine Plays a Critical Role in Regulating Cellular Adaptation to Glutamine Depletion

Abstract

SUMMARY Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

“…Light also could inhibit de novo purine synthesis by decreasing the amount of aspartate in the cell. Recent studies showed that decreases in nucleotide levels correlate with reduced synthesis of aspartate (52)(53)(54)(55)(56). These are reasonable mechanisms by which light could regulate de novo purine synthesis.…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Glutamine deprivation can directly lead to uncharged tRNAs, or lead to a depletion of downstream products such as asparagine to indirectly lead to uncharged tRNAs, all of which can activate GCN2 and induce ATF4 translation. Suppression of the ISR by glutamine input has been shown to be critical for survival of several cancer cell and tumor types including neuroblastoma and breast cancer 65,97,98 . It was also observed that GCN2 is activated in mice in response to treatment with asparaginase 99 , which is approved by the US Food and Drug Administration (FDA) for the treatment of acute lymphoblastic leukemia (ALL) and may deplete serum asparagine and glutamine [100][101][102] .…”

Glutamine at focus: versatile roles in cancer

“…Moreover, in certain K-ras-mutant cell lines, macropinocytosis can support uptake of extracellular protein to provide amino acid supplies (e.g., glutamine) for cell growth [41]. Conversely, some evidence suggests that the role of glutamine in anaplerosis is not the direct mechanism to avoid apoptosis, and that enhanced oxidation of branched chain amino acid (BCAA), as valine, leucine, and isoleucine, can also fuel tumor cells' bioenergetic demand [20]. This metabolic state of malignant cells challenges the current model and opens up interest to get a deeper understanding of this profound and intricate interplay between glutamine and cancer metabolic reprogramming.…”

“…In line with this notion, to investigate how glutamine catabolism can suppress apoptosis, Zhang et al screened by RNAi-based techniques factors what could protect Myc-transformed cells from apoptosis during glutamine withdrawal. The authors found that knockdown of citrate synthase (CS) resulted in redirection of OAA into aspartate and asparagines biosynthesis, blocking cell death [20].…”

“…Moreover, glutamine might be robustly correlated, rather than glucose, to maintain cancer invasion in ovarian tumor growth and in overall patient survival [19]. Conversely, an elegant observation has shown that other nutrients such as aspartate and asparagine can prevent cancer cell death during glutamine withdrawal [20]. Together, these findings are paving the way to understand glutamine metabolism and to exploit the metabolic nutrient state of susceptible populations of tumor cells for cancer therapy.…”