Abstract
Asparagine promotes the survival of cancer cells in response to glutamine withdrawal.
Major finding: Asparagine promotes the survival of cancer cells in response to glutamine withdrawal.
Mechanism: Asparagine suppresses the proapoptotic UPR mediator CHOP without restoring TCA cycle anaplerosis.
Impact: Inhibition of asparagine synthetase may be effective in solid tumors.
The growth and survival of cancer cells is dependent on extracellular glutamine, which is frequently depleted in solid tumors, resulting in the induction of apoptosis. Glutamine has been suggested to maintain cancer cell viability by replenishing intermediates for the tricarboxylic acid (TCA) cycle and supporting de novo biosynthesis of nucleotides and nonessential amino acids. Zhang and colleagues sought to characterize the mechanism by which glutamine withdrawal induces apoptosis using a high-throughput RNAi-based screen to identify genes whose loss protected MYC-transformed cells from apoptosis following glutamine withdrawal. Intriguingly, depletion of the TCA cycle enzyme citrate synthase (CS) protected cancer cells from glutamine withdrawal–induced cell death. In the absence of glutamine, knockdown of CS resulted in diminished glycolytic flux through the TCA cycle and redirection of the TCA cycle intermediate oxaloacetate to the synthesis of the nonessential amino acids aspartate and asparagine, suggesting that glutamine does not promote survival via maintenance of TCA cycle anaplerosis. Addition of asparagine was sufficient to restore cell viability following glutamine withdrawal, but did not alter cell proliferation or rescue TCA cycle intermediates or nonessential amino acid synthesis. Supporting the role of asparagine synthesis in the glutamine-dependent inhibition of apoptosis, knockdown of asparagine synthetase (ASNS) induced apoptosis even in the presence of glutamine, and ASNS expression was increased and correlated with poor prognosis in patients with high-grade glioma and neuroblastoma. The antiapoptotic function of asparagine was dependent on its ability to block induction of C/EBP-homologous protein (CHOP), a proapoptotic mediator of the unfolded protein response (UPR), without affecting induction of ASNS by activating transcription factor 4. In sum, these data demonstrate that asparagine is a critical regulator of cellular adaptation to glutamine withdrawal and suggest that inhibition of ASNS may have therapeutic benefit in solid tumors.
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