N-acetylaspartate improves cell survival when glucose is limiting

Abstract

N-acetylasparate (NAA), previously considered a brain-specific metabolite, is found in several cancers. However, whether it plays a role in tumor growth or survival is not fully understood. We provide evidence that NAA prevents cell death in low-glucose conditions via sustaining intracellular UDP-N-acetylglucosamine (UDP-GlcNac) levels, suppressing endoplasmic reticulum (ER) stress, and enabling continued protein synthesis. NAA production is critical for in vivo tumor growth where lower glucose levels are present than those in cell culture. Furthermore, the breakdown of NAA leads to ER stress and cell death, suggesting that the role of NAA in low-glucose is independent of its catabolism to produce aspartate or acetate. Together, these data suggest NAA can support the growth of some tumors by helping them cope with glucose limitations in vivo. HighlightsEndogenous N-acetylaspartate (NAA) production boosts tumor growth NAA supports cell survival in low glucose via suppressing ER stress Breaking down NAA limits tumor growth and induces ER stress in vivo The role of NAA to rescue low glucose is independent of donating acetate or aspartate In briefCancer cells need N-acetylaspartate to avoid ER stress and cell death when glucose availability is low.