Abstract
The epithelial signaling pathways involved in damage and regeneration, and neoplastic transformation are known to be similar. We noted upregulation of argininosuccinate synthetase (ASS1) in hyperproliferative intestinal epithelium. Since ASS1 leads to de novo synthesis of arginine, an important amino acid for the growth of intestinal epithelial cells, its upregulation can contribute to epithelial proliferation necessary to be sustained during oncogenic transformation and regeneration. Here we investigated the function of ASS1 in the gut epithelium during tissue regeneration and tumorigenesis, using intestinal epithelial conditional Ass1 knockout mice and organoids, and tissue specimens from colorectal cancer patients. We demonstrate that ASS1 is strongly expressed in the regenerating and Apc-mutated intestinal epithelium. Furthermore, we observe an arrest in amino acid flux of the urea cycle, which leads to an accumulation of intracellular arginine. However, loss of epithelial Ass1 does not lead to a reduction in proliferation or increase in apoptosis in vivo, also in mice fed an arginine-free diet. Epithelial loss of Ass1 seems to be compensated by altered arginine metabolism in other cell types and the liver.
Highlights
Epithelial tissues in healthy adult organs, such as the intestinal epithelium, are in a state of homeostasis, where the rates of cell division and cell death are in a dynamic equilibrium
Ass1 is highly expressed in repair of the intestinal epithelium and selectively upregulated in Apc-mutated organoids To investigate alterations in pathways associated with amino acid metabolism in the regenerating intestinal epithelium, we exposed mice to 14 Gy whole-body gamma irradiation (Fig. 1A)
Loss of Apc results in altered arginine metabolism In order to evaluate the effect of the Apc mutation in mouse intestinal epithelial organoids on arginine metabolism, we measured amino acid concentrations in the standard ENR medium of wild-type and Apc−/− organoids by HPLC
Summary
Epithelial tissues in healthy adult organs, such as the intestinal epithelium, are in a state of homeostasis, where the rates of cell division and cell death are in a dynamic equilibrium. Loss of epithelial cells by damage is rapidly compensated for by increased proliferation until the number of differentiated cells is restored and proliferation is reduced to homeostatic levels [1, 2]. This repair process is driven by repopulation of the stem cell pool by surviving stem cells, dedifferentiation of more committed progenitor cells that are able to adopt a stem cell phenotype and hyperproliferation [3, 4]. Because of the similarity between the mechanisms involved in regeneration and oncogenesis, understanding these metabolic changes in cancer could provide therapeutic targets for cancer, it may unveil treatment options for other diseases, like inflammatory bowel disease and several autoimmune disorders, which are characterized by impairment of the regeneration process and intestinal barrier function [14,15,16]
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