Asparagine Synthetase Is Highly Expressed at Baseline in the Pancreas Through Heightened PERK Signaling

Abstract

Asparaginase (ASNase) causes pancreatitis in approximately 10% of leukemia patients, and the mechanisms underlying this painful complication are not known. ASNase primarily depletes circulating asparagine, and the endogenously expressed enzyme, asparagine synthetase (ASNS), replenishes asparagine. ASNS was suggested previously to be highly expressed in the pancreas. In this study, we determined the expression pattern of ASNS in the pancreas and the mechanism for increased pancreatic ASNS abundance. Compared with other organs, ASNS was highly expressed in both the human and mouse pancreas, and, within the pancreas, ASNS was present primarily in the acinar cells. The high baseline pancreatic ASNS was associated with higher baseline activation of protein kinase R-like endoplasmic reticulum kinase (PERK) signaling in the pancreas, and inhibition of PERK in acinar cells lessened ASNS expression. ASNase exposure, but not the common pancreatitis triggers, uniquely up-regulated ASNS expression, indicating that the increase is mediated by nutrient stress. The up-regulation of acinar ASNS with ASNase exposure was owing to increased transcriptional rather than delayed degradation. Knockdown of ASNS in the 266-6 acinar cells provoked acinar cell injury and worsened ASNase-induced injury, whereas ASNS overexpression protected against ASNase-induced injury. In summary, ASNS is highly expressed in the pancreatic acinar cells through heightened basal activation of PERK, and ASNS appears to be crucial to maintaining acinar cell integrity. The implications are that ASNS is especially hardwired in the pancreas to protect against both baseline perturbations and nutrient deprivation stressors, such as during ASNase exposure.

A Practical Approach to Management of Acute Pancreatitis: Similarities and Dissimilarities of Disease in Children and Adults

“…Given the current viewpoint of shared disease models of inflammation and recovery, treatment recommendations are equivalent. However, emerging data on how drugs [34,35] and ERCP [36,37] induce pancreatic inflammation and affect tissue regeneration are highlighting new ways in which we may be able to design etiologyspecific AP risk models as well as treatments rather than a one size fits all approach [38].…”

Stress, nutrients and genotype: understanding and managing asparagine accumulation in wheat grain

“…In recent years, asparagine synthetase regulation in mammals has been of particular interest because of its relevance to cancer biology. The mammalian asparagine synthetase catalyses an identical reaction to the plant asparagine synthetase (Lomelino et al 2017) and its basal expression is low in all organs except for the pancreas, where it is important for protecting against nutrient stress (Mukherjee et al 2020). Asparagine synthetase gene expression in human tumour cells increases in response to glucose deprivation, glutamine deprivation, cisplatin treatment, and hypoxia (Cui et al 2007;Ameri et al 2010;Zhang et al 2014) and appears to play a role in cell proliferation (Gong and Basilico 1990).…”

Tumoral microenvironment prevents de novo asparagine biosynthesis in B cell lymphoma, regardless of ASNS expression

“…For that reason, we sought to determine in vivo the level of asparagine synthesis from carbon-labeled glutamine in mice bearing ASNS high -BCLs. As a positive control of endogenous ASNS activity, we also measured in vivo levels of asparagine synthesis in the organ with the highest ASNS expression (mRNA and protein) in mice and in humans, the pancreas ( 29 ). Therefore, Eμ- Myc –ASNS high cells arising from Eμ- Myc Tg/+ mice (#115) were injected into the tail vein of syngeneic WT C57Bl/6 mice.…”