| Abstract: |
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. |
| Keywords: |
genetics; cell proliferation; metabolism; cell survival; apoptosis; small interfering rna; rna, small interfering; rna interference; cell line, tumor; biosynthesis; chemistry; tumor cell line; activating transcription factor 4; aspartic acid; glutamine; asparagine; deficiency; citric acid cycle; protein bax; protein bak; bcl-2 homologous antagonist-killer protein; bcl-2-associated x protein; citrate synthase; humans; human; oxaloacetic acid; antagonists and inhibitors; aspartate ammonia ligase; atf4 protein, human; bak1 protein, human; bax protein, human; aspartate-ammonia ligase; citrate (si)-synthase
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